Tetracyclic compound

ABSTRACT

A compound represented by the general Formula (I) below, or a salt or solvate thereof, which is useful as an ALK inhibitor, and is useful for prophylaxis or treatment of a disease accompanied by abnormality in ALK, for example, cancer, cancer metastasis, depression or cognitive function disorder: 
     
       
         
         
             
             
         
       
         
         
           
             (meanings of the symbols that are included in the formula are as given in the specification).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/221,926, filed Jul. 28, 2016, which is a Continuation of U.S.application Ser. No. 14/619,242, filed Feb. 11, 2015, which is aDivisional of U.S. application Ser. No. 13/377,300, which is the U.S.National Stage application of PCT/JP2010/059785, filed Jun. 9, 2010,which claims priority from Japanese application JP 2009-139691, filedJun. 10, 2009.

TECHNICAL FIELD

The present invention relates to tetracyclic compounds, salts orsolvates thereof. More specifically, the present invention relates tothe tetracyclic compounds and provides a medicament, pharmaceuticalcompositions comprising the compounds, ALK inhibitors, andpharmaceuticals for the prophylaxis or treatment of the diseasesincluding cancer, cancer metastasis, depression or cognitive functiondisorder comprising the compounds. Furthermore, the present inventionrelates to a method for the treatment of the diseases comprisingadministering to the patient who is in need of the treatment of thedisease the compounds described herein, salts or solvates thereof in aneffective amount for the treatment of the diseases, and use of thetetracyclic compounds for the preparation of the pharmaceuticalcomposition.

BACKGROUND ART

Anaplastic Lymphoma Kinase (ALK) is one of the receptor tyrosine kinasesbelonging to insulin receptor family (Non-Patent Document Nos. 1 and 2).

It was reported that, due to gene alteration of ALK (translocation,point mutation and gene amplification), an abnormal activation of ALK iseventually involved in oncogenesis.

For example, in lung cancer, ALK forms EML4-ALK due to chromosomaltranslocation, leading to constitutive activation of tyrosine kinase,and it acquires a tumorigenic activity (Non-Patent Document 1). Inaddition, the ALK translocation were reported in systemic anaplasticlarge cell lymphoma (ALCL) and inflammatory myofibroblastic tumors(IMTs) (Non-Patent Document Nos. 3 and 4), and esophageal cancer(Non-Patent Document 5). It was also found that active point mutation(approximately 10%) or gene amplification of ALK is involved inoncogenesis of neuroblastoma (Non-Patent Document Nos. 6 and 7).

On the other hand, it was also reported in tumors activated bypleiotrophin (PTN) or midkine (MK) (Non-Patent Document Nos. 8 and 9),both a ligand for ALK.

Further, from the study using ALK knock-out mouse, it was suggested thatan inhibitor for ALK is useful as an anti-depression agent or as apreventive or therapeutic agent for cognitive function disorders(Non-Patent Document 10 and Patent Document 1).

Therefore, a compound having an inhibitory activity on ALK will be veryuseful for the prevention and treatment of cancer, depression andcognitive function disorders, etc.

Meanwhile, as an ALK inhibiting material, there are some compounds amongmulti-kinase inhibitors which have an inhibitory activity on ALK as oneof their activities. For example, as an inhibitor for c-MET(mesenchymal-epithelial transition factor) and ALK, PF02341066 having a2-aminopyridine structure was reported (Patent Document 2, Non-PatentDocument Nos. 11 and 12). As an inhibitor for FAK, ZAP70, IGF-1R andALK, etc., NVP-TAE684 having a 2,4-diaminopyrimidine structure wasreported (Patent Document 3 and Non-Patent Document 13). In addition,2,4-diaminopyrimidines and 2,4-diaminoquinazolines (Patent Document 4),pyridopyrazines (Patent Document 5), pyrazolo [3,4-C] isoquinolines(Patent Document 6), thiazoles (Patent Document 7), tricyclic compounds(Patent Document 8), and indazoles (Patent Document 9) and the like havebeen reported.

However, the tetracyclic compounds of the present invention are notdisclosed in any of the documents described above.

As a tetracyclic compound exhibiting an anti-tumor activity, tetracycliccompounds comprising carbazole structure like ellipticine are known.

However, their action mechanism is based on interaction with DNA toexhibit cell toxicity (Non-Patent Document 15), and there is nodescription at all regarding the activity of inhibiting ALK by thetetracyclic compounds.

DOCUMENT LIST

-   [Patent Document 1] WO 2007/023310 A2-   [Patent Document 2] WO 2006/021884 A2-   [Patent Document 3] WO 2004/080980 A1-   [Patent Document 4] WO 2009/008371 A1-   [Patent Document 5] WO 2007/130468 A2-   [Patent Document 6] WO 2005/009389 A2-   [Patent Document 7] WO 2005/097765 A1-   [Patent Document 8] WO 2008/021369 A2-   [Patent Document 9] WO 2009/013126 A1-   [Non-Patent Document 1] Proc Natl Acad Sci USA, Vol. 101, pages    13306-13311, 2004-   [Non-Patent Document 2] Nature, Vol. 448, pages 561-566, 2007-   [Non-Patent Document 3] Blood, Vol. 72, pages 234-240, 1988-   [Non-Patent Document 4] Cancer Res, Vol. 59, pages 2776-2780, 1999-   [Non-Patent Document 5] World J Gastroenterol, Vol. 12, pages    7104-7112, 2006-   [Non-Patent Document 6] Nature, Vol. 455, pages 930-935, 2008-   [Non-Patent Document 7] Nature, Vol. 455, pages 971-974, 2008-   [Non-Patent Document 8] J Biol Chem, Vol. 276, pages 16772-16779,    2001-   [Non-Patent Document 9] J Biol Chem, Vol. 277, pages 35990-35999,    2002-   [Non-Patent Document 10] Neuropsychopharmacology, Vol. 33, pages    685-700, 2008-   [Non-Patent Document 11] Proc Am Assoc Cancer Res (AACR) 2006, 47:    Abst LB-271-   [Non-Patent Document 12] Proc Am Assoc Cancer Res (AACR) 2006, 47:    Abst LB-273-   [Non-Patent Document 13] Proc Natl Acad Sci USA Vol. 104, pages    270-275, 2007-   [Non-Patent Document 14] Current Organic Chemistry, Vol. 5, Issue    No. 5, pages 507-518, 2001-   [Non-Patent Document 15] Current Medicinal Chemistry: Anti-Cancer    Agents, Vol. 4, Issue No. 2, pages 149-172, 2004

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention is to provide ALK-inhibiting compounds having anovel structure. In addition, object of the present invention is toprovide a pharmaceuticals for the prophylaxis or treatment comprisingthe ALK-inhibiting compounds that is effective for prophylaxising ortreating a disease accompanied by abnormality in ALK, for example,cancer, cancer metastasis, depression and cognitive function disorder.

Means for Solving the Problems

As a result of extensive studies by the inventors of the presentinvention, it was found that the tetracyclic compounds that arerepresented by the following Formula (1) with a structure clearlydifferent from any other existing pharmaceutical compounds have anexcellent ALK-inhibiting activity, are useful for the treatment andprophylaxis of the diseases including cancer, cancer metastasis,depression and cognitive function disorder, and have a remarkableefficacy against said diseases. Accordingly, the present invention wascompleted.

Thus, according to one aspect of the present invention, the tetracycliccompounds, a medicament and a pharmaceutical composition comprising thecompounds, etc. shown below are provided.

[1] A compound or salt or solvate thereof represented by Formula (I):

[wherein,

-   -   A¹, A², A³, A⁴, A⁷, A⁸, A⁹ and A¹⁰ all represent C, or any one        of A², A³, A⁴, A⁸ and A⁹ represents N (with the proviso that,        when it represents N, no substituent group exists therefor) and        the remainings represent C;    -   A⁵ is selected from NR⁵, O and S;    -   R¹ and R¹⁰ each independently represent [1] a hydrogen atom, [2]        a cyano group, [3] a halogen atom or [4] a 4- to 10-membered        heterocycloalkyl group which may be substituted by 4- to        10-membered heterocycloalkyl group(s);    -   R² is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group,    -   (3) a C₂₋₈ alkenyl group,    -   (4) a C₂₋₈ alkynyl group,    -   (5) a cyano group,    -   (6) a halogen atom,    -   (7) a (C₁₋₈ alkyl)_(m2)-amino group which may be substituted by        C₁₋₈ alkylsulfonyl group(s),        -   m2: 0˜2, and    -   (8) a nitro group;        -   R³ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by [1] halogen        atom(s), [2]hydroxy group(s) or [3] C₁₋₈ alkoxy group(s),    -   (3) a C₆₋₁₀ aryl group,    -   (4) a cyano group,    -   (5) a C₁₋₈ alkanoyl group which may be substituted by C₆₋₁₀ aryl        group(s),    -   (6) a (C1-8 alkyl)_(m3a)-aminocarbonyl group which may be        substituted by one or more R^(3A),    -   R^(3A): [1] a C₆₋₁₀ aryl group, [2] a C₁₋₈ alkoxy group, [3] a        5- to 14-membered heteroaryl group, or [4] a C₆₋₁₀ aryl sulfonyl        group,    -   m3a: 0˜2,    -   (7) a hydroxycarbonyl group,    -   (8) a C₁₋₈ alkoxycarbonyl group which may be substituted by [1]        hydroxy group(s) or [2] C₁₋₈ alkoxy group(s),    -   (9) a halogen atom,    -   (10) a (C₁₋₈ alkyl)_(m3b)-amino group which may be substituted        by C₆₋₁₀ aryl group(s),        -   m3b: 0˜2,    -   (11) a C₁₋₈ alkylcarbonyl (C₀₋₈ alkyl) amino group which may be        substituted by [1]C₆₋₁₀ aryl group(s) or [2] C₆₋₁₀ aryloxy        group(s),    -   (12) a C₆₋₁₀ arylcarbonyl (C₀₋₈ alkyl) amino group which may be        substituted by C₁₋₈ alkyl group(s) which may be substituted by        halogen atom(s),    -   (13) a (C₁₋₈ alkyl)_(m3c)-aminocarbonyl (C₀₋₈ alkyl) amino group        which may be substituted by C₆₋₁₀ aryl group(s),        -   m3c: 0˜2,    -   (14) a nitro group,    -   (15) a hydroxy group,    -   (16) a C₁₋₈ alkoxy group which may be substituted by one or more        R^(3B),    -   R^(3B): [1] a hydroxy group, [2] a C₁₋₈ alkoxy group, [3] a        C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl group, [4] a (C₁₋₈        alkyl)_(m3d)-amino group, or [5] a halogen atom,        -   m3d: 0˜2,    -   (17) a 4- to 10-membered heterocycloalkyloxy group,    -   (18) a 5- to 14-membered heteroaryloxy group,    -   (19) a (C₁₋₈ alkyl)_(m3e)-aminocarbonyloxy group which may be        substituted by C₆₋₁₀ aryl group(s)        -   m3e: 0˜2,    -   (20) a 4- to 10-membered nitrogen-containing        heterocycloalkylcarbonyl group,    -   (21) a C₁₋₈ alkylsulfonyloxy group which may be substituted by        halogen atom(s),    -   (22) a C₁₋₈ alkylthio group,    -   (23) a C₁₋₈ alkylsulfonyl group which may be substituted by        C₆₋₁₀ aryl group(s),    -   (24) a 5- to 14-membered heteroaryl group which may be        substituted by C₁₋₈ alkyl group(s) which may be substituted by        C₁₋₈ alkoxy group(s),    -   (25) a C₁₋₈ alkoxycarbonyl (C₀₋₈ alkyl) amino group which may be        substituted by C₁₋₈ alkoxy group(s),    -   (26) a C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl) amino group which may        be substituted by C₁₋₈ alkyl group(s) which may be substituted        by halogen atom(s),    -   (27) a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈ alkyl) amino        group which may be substituted by one or more R^(3C),    -   R^(3C): [1] a C₁₋₈ alkyl group which may be substituted by        halogen atom(s), or [2] a C₁₋₈ alkoxy group,    -   (28) a C₃₋₈ cycloalkyl (C₀₋₈ alkyl) aminocarbonyloxy group, and    -   (29) a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyloxy group which may        be substituted by substituent(s) selected from the group        consisting of [1] a C₁₋₈ alkyl group and [2] a C₁₋₈ alkoxy        group;    -   R⁴ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by halogen        atom(s),    -   (3) a C₂₋₈ alkenyl group,    -   (4) a C₂₋₈ alkynyl group,    -   (5) a C₃₋₈ cycloalkyl group,    -   (6) a cyano group,    -   (7) an aminocarbonyl group,    -   (8) a (C₁₋₈ alkyl)_(m4a)-aminocarbonyl group,        -   m4a: 1˜2,    -   (9) a hydroxycarbonyl group,    -   (10) a C₁₋₈ alkoxycarbonyl group,    -   (11) a halogen atom,    -   (12) a (C₁₋₈ alkyl)_(m4b)-amino group,        -   m4b: 0˜2,    -   (13) a hydroxy group, and    -   (14) a C₁₋₈ alkoxy group which may be substituted by hydroxy        group(s);    -   R⁵ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by one or more        R^(5A),    -   R^(5A): [1] a hydroxycarbonyl group, [2] a C₁₋₈ alkoxycarbonyl        group, [3] a hydroxy group, [4] a C₁₋₈ alkoxy group, [5] a (C₁₋₈        alkyl)_(m5)-amino group, [6] a C₆₋₁₀ aryl group, or [7] a C₁₋₈        alkylthio group,        -   m5: 0˜2,    -   (3) a C₂₋₈ alkenyl group,    -   (4) a C₂₋₈ alkynyl group,    -   (5) a C₃₋₈ cycloalkyl group, and    -   (6) a C₁₋₈ alkylsulfonyl group;    -   R⁶ and R^(6′) are each independently selected from the group        consisting of:    -   (1) a C₁₋₈ alkyl group which may be substituted by halogen        atom(s),    -   (2) a C₂₋₈ alkenyl group, and    -   (3) a C₂₋₈ alkynyl group; or    -   R⁶ and R^(6′) are taken together with the carbon atoms to which        they are bound to form:    -   (4) a C₃₋₈ cycloalkyl group, or    -   (5) a 4- to 10-membered heterocycloalkyl group which may be        substituted by C₁₋₈ alkyl C₆₋₁₀ aryl sulfonyl group(s) which may        be substituted by C₁₋₈ alkyl group(s);    -   R⁷ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a halogen atom,    -   (3) a C₁₋₈ alkoxy group which may be substituted by one or more        R^(7A),    -   R^(7A): [1] a (C₁₋₈ alkyl)_(m7a)-amino group, [2] a hydroxy, [3]        a 4- to 10-membered heterocycloalkyl group which may be        substituted by C₁₋₈ alkyl group(s),    -   m7a: 0˜2,    -   (4) a C₁₋₈ alkylsulfonyl group,    -   (5) a nitro group, and    -   (6) a hydroxyl group;    -   R⁸ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by one or more        R^(8A),    -   R^(8A): [1] a 4- to 10-membered heterocycloalkyl group which may        be substituted by one or more R^(8A1), [2] a (C₁₋₈        alkyl)_(m8a)-amino group which may be substituted by a halogen        atom, and [3] a hydroxy group,        -   m8a: 0˜2,    -   R^(8A1): [1] a C₁₋₈ alkyl group, [2] a C₁₋₈ alkylsulfonyl group,        [3] a (C₁₋₈ alkyl)_(m8b)-aminosulfonyl group, [4] an oxo group,        [5] a C₁₋₈ alkoxycarbonyl, or [6] a C₁₋₈ alkoxycarbonyl (C₀₋₈        alkyl) aminosulfonyl,        -   m8b: 0˜2,    -   (3) a C₂₋₈ alkenyl group,    -   (4) a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(8B),    -   R^(8B):        <1> a C₁₋₈ alkyl group which may be substituted by one or more        R^(8B1),        <2> a C₂₋₈ alkenyl group,        <3> a C₂₋₈ alkynyl group,        <4> a C₃₋₈ cycloalkyl group which may be substituted by [1]        cyano group(s) or [2] C₁₋₈ alkyl group(s),        <5> a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(8B2),        <6> a C₁₋₈ alkoxy group which may be substituted by        substituent(s) selected from the group consisting of [1] a C₁₋₈        alkoxy group and [2] a C₃₋₈ cycloalkyl group,        <7> a C₁₋₈ alkoxycarbonyl group,        <8> a C₁₋₈ alkylsulfonyl group,        <9> a 5- to 14-membered heteroarylsulfonyl group,        <10> an oxo group,        <11> a cyano group,        <12> a C₁₋₈ alkanoyl group which may be substituted by one or        more R^(8B3),        <13> a C₃₋₈ cycloalkylcarbonyl group,        <14> a (C₁₋₈ alkyl)_(m8c)-aminosulfonyl group,        <15> a C₁₋₈ alkylsulfonyl (C₀₋₈ alkyl) amino group,        <16> a (C₁₋₈ alkyl)_(m8d)-amino group which may be substituted        by one or more R^(8B4),        <17> a hydroxy group,        <18> a (C₁₋₈ alkyl)_(m8e)-aminocarbonyl group, or        <19> a C₁₋₈ alkoxycarbonyl (C₀₋₈ alkyl) amino group    -   m8c: 0˜2    -   m8d: 0˜2    -   m8e: 0˜2    -   R^(8B1): [1] a C₃₋₈ cycloalkyl group, [2] a hydroxy group, or        [3] a C₁₋₈ alkoxy group(s),    -   R^(8B2): [1] a halogen atom, [2] a C₁₋₈ alkyl group, [3] an oxo        group, [4] a hydroxy group, or [5] a deuterium atom,    -   R^(8B3): a (C₁₋₈ alkyl)_(m8f)-amino group,        -   m8f: 0˜2,    -   R^(8B4): [1] a C₃₋₈ cycloalkyl group, or [2] a hydroxy group,    -   (5) a 5- to 14-membered heteroaryl group which may be        substituted by a C₁₋₈ alkyl group,    -   (6) a (C₁₋₈ alkyl)_(m8g)-aminocarbonyl group which may be        substituted by one or more R^(8C),        -   m8g: 0˜2,    -   R^(8C): [1] a hydroxy group, [2] a (C₁₋₈ alkyl)_(m8h)-amino        group which may be substituted by substituent(s) selected from        the group consisting of <1> a (C₁₋₈ alkyl)_(m8i)-aminosulfonyl        group, <2> a C₁₋₈ alkylsulfonyl group, <3> a C₁₋₈ alkoxycarbonyl        group and <4> a C₁₋₈ alkoxycarbonyl(C₀₋₈ alkyl) aminosulfonyl        group, [3] a C₁₋₈ alkylsulfonyl group, or [4] a C₁₋₈ alkoxy        group which may be substituted by a hydroxy group,        -   m8h: 0˜2,        -   m8i: 0˜2,    -   (7) a 4- to 10-membered heterocycloalkyl (C₀₋₈ alkyl)        aminocarbonyl group which may be substituted by oxo group(s),    -   (8) a 4- to 10-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by one        or more R^(8D),    -   R^(8D): [1] a C₁₋₈ alkyl group which may be substituted by one        or more R^(8D1), [2] a hydroxy group, [3] a C₁₋₈ alkylsulfonyl        group, or [4] a C₁₋₈ alkoxycarbonyl group,    -   R^(8D1): [1] a hydroxy group, or [2] a C₁₋₈ alkoxy group,    -   (9) a hydroxycarbonyl group,    -   (10) a C₀₋₈ alkoxy (C₀₋₈ alkyl) aminocarbonyl group which may be        substituted by hydroxy group(s),    -   (11) a halogen atom,    -   (12) a (C₁₋₈ alkyl)_(m8j)-amino group which may be substituted        by one or more R^(8H),        -   m8j: 0˜2,        -   R^(8H): [1] a hydroxy group, or [2] a 4- to 10-membered            heterocycloalkyl group,    -   (13) a hydroxyl group,    -   (14) a C₁₋₈ alkoxy group which may be substituted by one or more        R^(8E),    -   R^(8E):        <1> a hydroxy group,        <2> halogen atom,        <3> a hydroxycarbonyl group,        <4> a C₁₋₈ alkoxycarbonyl group,        <5> a 4- to 10-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by one        or more R^(8E1),        <6> a (C₁₋₈ alkyl)_(m8k1)-amino group which may be substituted        by one or more R^(8E2),    -   m8k1: 0˜2,        <7> a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(8E3),        <8> a 5- to 14-membered heteroaryl group,        <9> a (C₁₋₈ alkyl)_(m8k2)-aminocarbonyl group which may be        substituted by one or more R^(8E6),    -   m^(8k2): 0˜2,        <10> a C₁₋₈ alkoxy group which may be substituted by one or more        R^(8E7),        <11> a C₁₋₈ alkylthio group,        <12> a C₁₋₈ alkylsulfinyl group,        <13> a C₁₋₈ alkylsulfonyl group,    -   R^(8E1):        <1> a C₁₋₈ alkoxycarbonyl group,        <2> a C₁₋₈ alkanoyl group,        <3> a C₁₋₈ alkylsulfonyl group,        <4> a (C₁₋₈ alkyl)_(m8k3)-aminosulfonyl group,    -   m8k3: 0˜2, or        <5> a 4- to 10-membered heterocycloalkyl group,    -   R^(8E2):        <1> a hydroxy group,        <2> a C₁₋₈ alkoxycarbonyl group which may be substituted by        halogen atom(s),        <3> a C₃₋₈ cycloalkyl group which may be substituted by C₁₋₈        alkyl group(s) which may be substituted by hydroxy group(s),        <4> a C₁₋₈ alkanoyl group which may be substituted by        substituent(s) selected from the group consisting of [1] a (C₁₋₈        alkyl)_(m8k4)-amino group and [2] a halogen atom(s),    -   m8k4: 0˜2,        <5> a (C₁₋₈ alkyl)_(m8k5)-aminocarbonyl group,    -   m8k5: 0˜2,        <6> a C₁₋₈ alkylsulfonyl group,        <7> a 4- to 10-membered nitrogen-containing        heterocycloalkylsulfonyl group which may be substituted by C₁₋₈        alkyl group(s),        <8> a (C₁₋₈ alkyl)_(m8k6)-aminosulfonyl group which may be        substituted by C₁₋₈ alkoxycarbonyl group(s),    -   m8k6: 0˜2, or    -   R^(8E3):        <1> a C₁₋₈ alkyl group which may be substituted by        substituent(s) selected from the group consisting of [1] a        hydroxy group and [2] a C₁₋₈ alkylcarbonyloxy group,        <2> a C₁₋₈ alkylcarbonyloxy group,        <3> a hydroxy group,        <4> a C₃₋₈ cycloalkyl group,        <5> a C₁₋₈ alkoxy group,        <6> a C₁₋₈ alkoxycarbonyl group,        <7> a C₁₋₈ alkylsulfonyl group,        <8> a (C₁₋₈ alkyl)_(m8k8)-aminocarbonyl group    -   m8k8: 0˜2,        <9> a C₁₋₈ alkanoyl group which may be substituted by hydroxy        group(s),        <10> an oxo group, or        <11> a 4- to 10-membered heterocycloalkyl group which may be        substituted by substituent(s) selected from the group consisting        of [1] a C₁₋₈ alkanoyl group, [2] a C₁₋₈ alkoxycarbonyl group        and [3] a C₁₋₈ alkylsulfonyl group,    -   R^(8E6):        <1> a C₂₋₈ alkenylcarbonyloxy group,        <2> a hydroxy group,        <3> a cyano group,        <4> a (C₁₋₈ alkyl)_(m8k9)-amino group which may be substituted        by hydroxy group(s)    -   m8k9: 0˜2,        <5> a C₁₋₈ alkoxy group which may be substituted by hydroxy        group(s),        <6> a C₁₋₈ alkylcarbonyloxy group,        <7> a 4- to 10-membered heterocycloalkyl group which may be        substituted by C₁₋₈ alkyl group(s), or        <8> a 5- to 14-membered heteroaryl group,    -   R^(8E7):        <1> a hydroxy group, or        <2> a C₁₋₈ alkoxy group which may be substituted by hydroxy        group(s),    -   (15) a 4- to 10-membered heterocycloalkyloxy group which may be        substituted by one or more R^(8F),    -   R^(8F):        <1> a C₁₋₈ alkyl group which may be substituted by one or more        R^(8F1),        <2> a C₃₋₈ cycloalkyl group,        <3> a C₁₋₈ alkanoyl group which may be substituted by halogen        atom(s),        <4> a C₁₋₈ alkylcarbonyloxy group,        <5> a C₁₋₈ alkoxycarbonyl group,        <6> a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(8F2),        <7> a C₁₋₈ alkyl sulfonyl group,        <8> a hydroxy group, or        [9] a C₆₋₁₀ aryl group,    -   R^(8F1): [1] a hydroxy group, [2] a C₁₋₈ alkoxy group, or [3] a        halogen atom,    -   R^(8F2): [1] a 4- to 10-membered heterocycloalkyl group, [2] a        C₁₋₈ alkoxycarbonyl group, or [3] a C₁₋₈ alkylsulfonyl group,    -   (16) a 5- to 14-membered heteroaryloxy group,    -   (17) a 4- to 10-membered heterocycloalkylcarbonyloxy group,    -   (18) a (C₁₋₈ alkyl)_(m8l1)-aminosulfonyloxy group,        -   m8l1: 0˜2,    -   (19) a C₁₋₈ alkyl thio group which may be substituted by [1]        (C₁₋₈ alkyl)_(m8l2)-amino group(s), [2] hydroxy group(s) or [3]        hydroxycarbonyl group(s),        -   m8l2: 0˜2,    -   (20) a C₁₋₈ alkylsulfonyl group which may be substituted by one        or more R^(8G),    -   R^(8G): [1] a hydroxycarbonyl group, [2] a hydroxy group, or [3]        a (C₁₋₈ alkyl)_(m8l3)-amino group,        -   m8l3: 0˜2,    -   (21) a 4- to 10-membered nitrogen-containing        heterocycloalkylsulfonyloxy group which may be substituted by        C₁₋₈ alkyl group(s),    -   (22) a C₂₋₈ alkenyloxy group, and    -   (23) a C₁₋₈ alkylsulfonyloxy group which may be substituted by        halogen atom(s);    -   R⁹ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by one or more        R^(9A),    -   R^(9A): [1] a C₃₋₈ cycloalkyl group, [2] a 4- to 10-membered        heterocycloalkyl group which may be substituted by one or more        R^(9A1), [3] a hydroxy group, [4] a C₁₋₈ alkoxy group, or [5] a        hydroxycarbonyl group,    -   R^(9A1): [1] a C₁₋₈ alkyl group, [2] a C₃₋₈ cycloalkyl group, or        [3] a 4- to 10-membered heterocycloalkyl group,    -   (3) a C₂₋₈ alkenyl group which may be substituted by one or more        R^(9B),    -   R^(9B): [1] a (C₁₋₈ alkyl)_(m9a)-amino group, [2] a 4- to        10-membered heterocycloalkyl group which may be substituted by        one or more group R^(9B1),    -   R^(9B1): [1] a C₃₋₈ cycloalkyl group, or [2] a 4- to 10-membered        heterocycloalkyl group,        -   m9a: 0˜2,    -   (4) a C₂₋₈ alkynyl group which may be substituted by one or more        R^(9C),    -   R^(9C): [1] a C₁₋₈ alkoxy group, [2] a (C₁₋₈ alkyl)_(m9b)-amino        group which may be substituted by C₆₋₁₀ aryl group(s), [3] a 4-        to 10-membered heterocycloalkyl group which may be substituted        by one or more R^(9C1), [4] a C₃₋₈ cycloalkyl group, [5] a        hydroxy group, [6] a hydroxycarbonyl group, or [7] a C₁₋₈        alkyloxycarbonyl group,        -   m9b: 0˜2,    -   R^(9C1): [1] a C₃₋₈ cycloalkyl group, [2] a 4- to 10-membered        heterocycloalkyl group, or [3] an oxo group,    -   (5) a C₃₋₈ cycloalkyl group,    -   (6) a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(9D),    -   R^(9D): [1] a C₁₋₈ alkyl group which may be substituted by 4- to        10-membered heterocycloalkyl group(s), [2] a C₃₋₈ cycloalkyl        group, [3] a 4- to 10-membered heterocycloalkyl group, or [4] a        C₁₋₆ alkylsulfonyl group, or [5] a C₁₋₈ alkoxycarbonyl group,    -   (7) a C₆₋₁₀ aryl group which may be substituted by one or more        R^(9E),    -   R^(9E): [1] a halogen atom, [2] a hydroxy group, [3] a        hydroxycarbonyl group, or [4] a C₁₋₈ alkyl group which may be        substituted by hydroxy group(s), or [5] a C₁₋₈ alkoxy group,    -   (8) a 5- to 14-membered heteroaryl group which may be        substituted by C₁₋₈ alkyl group(s),    -   (9) a cyano group,    -   (10) a C₁₋₈ alkanoyl group,    -   (11) a 4- to 10-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by C₁₋₈        alkyl group(s),    -   (12) a halogen atom,    -   (13) a (C₁₋₈ alkyl)_(m9c)-amino group which may be substituted        by one or more R^(9F),        -   m9c: 0˜2,    -   (14) a C₁₋₈ alkylcarbonyl(C₀₋₈ alkyl)amino group which may be        substituted by (C₁₋₈ alkyl)_(m9d)-amino group(s),        -   m9d: 0˜2,    -   (15) a C₁₋₈ alkylsulfonyl(C₀₋₈ alkyl)amino group,    -   (16) a (C₁₋₈ alkyl)_(m9e)-aminosulfonyl(C₀₋₈ alkyl)amino group,        -   m9e: 0˜2,    -   (17) a nitro group,    -   (18) a hydroxy group,    -   (19) a C₁₋₈ alkoxy group which may be substituted by one or more        R^(9G),    -   R^(9G): [1] a hydroxy group, [2] a hydroxycarbonyl group, [3] a        C₆₋₁₀ aryl group which may be substituted by C₁₋₈ alkoxy        group(s), [4] a (C₁₋₈ alkyl)_(m9g1)-amino group, [5] a C₁₋₈        alkoxy group which may be substituted by one or more R^(9G1),        [6] a 5- to 14-membered heteroaryl group, or [7] a 4- to        10-membered heterocycloalkyloxy group which may be substituted        by C₁₋₈ alkyl group(s),        -   m9g1: 0˜2,    -   R^(9G1): [1] a C₁₋₈ alkoxy group, or [2] a hydroxycarbonyl        group,    -   (20) a 4- to 10-membered heterocycloalkyloxy group which may be        substituted by [1] 4- to 10-membered heterocycloalkyl group(s),        or [2] C₁₋₈ alkoxycarbonyl group(s),    -   (21) a C₁₋₈ alkylsulfonyloxy group which may be substituted by        halogen atom(s),    -   (22) a C₁₋₈ alkylthio group which may be substituted by (C₁₋₈        alkyl)_(m9f)-amino group(s),        -   m9f: 0˜2,    -   (23) a C₁₋₈ alkylsulfonyl group which may be substituted by        (C₁₋₈ alkyl)_(m9g)-amino group(s),        -   m9g: 0˜2,    -   (24) a (C₁₋₈ alkyl)_(m9h)-aminosulfonyl group,        -   m9h: 0˜2,    -   (25) a 4- to 10-membered nitrogen-containing        heterocycloalkylsulfonyl group which may be substituted by C₁₋₈        alkyl group(s), and    -   (26) a hydroxycarbonyl group].        [2] The compound according to the above [1], or a salt or        solvate thereof, wherein R³ is a cyano group or a halogen atom.        [3] The compound according to the above [1], or a salt or        solvate thereof, wherein A⁵ is NR⁵ and R⁵ is a hydrogen atom.        [4] The compound according to the above [1], or a salt or        solvate thereof, wherein all of the A¹, A², A³, A⁴, A⁷, A⁸, A⁹        and A¹⁰ are a carbon atom.

[5] The compound according to claim 1, or a salt or solvate thereof,wherein:

A¹, A², A³, A⁴, A⁷, A⁸, A⁹ and A¹⁰ all represent C, or any one of A²,A³, A⁴, A⁷, A⁸ and A⁹ represents N (with the proviso that, when itrepresents N, no substituent group exists therefor) and the remainingsrepresent C;

-   -   A⁵ is selected from NR⁵, O and S;    -   R¹ represents [1] a hydrogen atom, [2] a cyano group, or [3] a        halogen atom;    -   R² is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group,    -   (3) a cyano group,    -   (4) a halogen atom, and    -   (5) a (C₁₋₈ alkyl)_(m2)-amino group which may be substituted by        C₁₋₈ alkylsulfonyl group(s),        -   m2: 0˜2;        -   R³ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by halogen        atom(s),    -   (3) a cyano group,    -   (4) a (C₁₋₈ alkyl)_(m3a)-aminocarbonyl group which may be        substituted by one or more R^(3A),    -   R^(3A): [1] a C₆₋₁₀ aryl group, [2] a C₁₋₈ alkoxy group, [3] a        5- to 14-membered heteroaryl group, or [4] a C₆₋₁₀ aryl sulfonyl        group,        -   m3a: 0˜2,    -   (5) a hydroxycarbonyl group,    -   (6) a C₁₋₈ alkoxycarbonyl group which may be substituted by        hydroxy group(s),    -   (7) a halogen atom,    -   (8) a (C₁₋₈ alkyl)_(m3b)-amino group which may be substituted by        C₆₋₁₀ aryl group(s),        -   m3b: 0˜2,    -   (9) a C₁₋₈ alkylcarbonyl (C₀₋₈ alkyl) amino group which may be        substituted by [1]C₆₋₁₀ aryl group(s) or [2] C₆₋₁₀ aryloxy        group(s),    -   (10) a C₆₋₁₀ arylcarbonyl (C₀₋₈ alkyl) amino group which may be        substituted by C₁₋₈ alkyl group(s) which may be substituted by        halogen atom(s),    -   (11) a nitro group,    -   (12) a hydroxy group,    -   (13) a C₁₋₈ alkoxy group which may be substituted by one or more        R^(3B),    -   R^(3B): [1] a hydroxy group, [2] a C₁₋₈ alkoxy group, [3] a        C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl group, [4] a (C₁₋₈        alkyl)_(m3d)-amino group, or [5] a halogen atom,        -   m3d: 0˜2,    -   (14) a 4- to 10-membered heterocycloalkyloxy group,    -   (15) a 5- to 14-membered heteroaryloxy group,    -   (16) a (C₁₋₈ alkyl)_(m3e)-aminocarbonyloxy group which may be        substituted by C₆₋₁₀ aryl group(s),        -   m3e: 0˜2,    -   (17) a 4- to 10-membered nitrogen-containing        heterocycloalkylcarbonyl group,    -   (18) a C₁₋₈ alkylthio group,    -   (19) a 5- to 14-membered heteroaryl group which may be        substituted by C₁₋₈ alkyl group(s) which may be substituted by        C₁₋₈ alkoxy group(s),    -   (20) a C₁₋₈ alkoxycarbonyl (C₀₋₈ alkyl) amino group which may be        substituted by C₁₋₈ alkoxy group(s),    -   (21) a C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl) amino group which may        be substituted by C₁₋₈ alkyl group(s) which may be substituted        by halogen atom(s),    -   (22) a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈ alkyl) amino        group which may be substituted by C₁₋₈ alkoxy group(s),    -   (23) a C₃₋₈ cycloalkyl (C₀₋₈ alkyl) aminocarbonyloxy group, and    -   (24) a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyloxy group which may        be substituted by substituent(s) selected from the group        consisting of [1] a C₁₋₈ alkyl group and [2] a C₁₋₈ alkoxy        group;    -   R⁴ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by halogen        atom(s),    -   (3) a C₃₋₈ cycloalkyl group,    -   (4) a cyano group,    -   (5) an aminocarbonyl group,    -   (6) a hydroxycarbonyl group,    -   (7) a halogen atom,    -   (8) a (C₁₋₈ alkyl)_(m4b)-amino group,        -   m4b: 0˜2,    -   (9) a hydroxy group, and    -   (10) a C₁₋₈ alkoxy group which may be substituted by hydroxy        group(s);    -   R⁵ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by one or more        R^(5A),    -   R^(5A): [1] a hydroxycarbonyl group, [2] a C₁₋₈ alkoxycarbonyl        group, [3] a hydroxy group, [4] a C₁₋₈ alkoxy group, [5] a (C₁₋₈        alkyl)_(m5)-amino group, or [6], a C₁₋₈ alkylthio group,        -   m5: 0˜2, and    -   (3) a C₁₋₈ alkylsulfonyl group;    -   R⁶ and R^(6′) are each independently:    -   (1) a C₁₋₈ alkyl group, or    -   R⁶ and R^(6′) are taken together with the carbon atoms to which        they are bound to form,    -   (2) a C₃₋₈ cycloalkyl group, or    -   (3) a 4- to 10-membered heterocycloalkyl group;    -   R⁷ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a halogen atom, and    -   (3) a C₁₋₈ alkoxy group which may be substituted by one or more        R^(7A),        R^(7A): [1] a (C₁₋₈ alkyl)_(m7a)-amino group, or [2] a hydroxy        group,    -   m7a: 0-2;    -   R⁸ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by one or more        R^(8A),    -   R^(8A): [1] a 4- to 10-membered heterocycloalkyl group which may        be substituted by one or more R^(8A1), [2] a (C₁₋₈        alkyl)_(m8a)-amino group which may be substituted by a halogen        atom, and [3] a hydroxy group,        -   m8a: 0-2,    -   R^(8A1): [1] a C₁₋₈ alkyl group, [2] a C₁₋₈ alkylsulfonyl group,        [3] a (C₁₋₈ alkyl)_(m8b)-aminosulfonyl group, or [4] an oxo        group,        -   m8b: 0˜2,    -   (3) a C₂₋₈ alkenyl group,    -   (4) a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(8B),    -   R^(8B):        <1> a C₁₋₈ alkyl group which may be substituted by one or more        R^(8B1),        <2> a C₂₋₈ alkynyl group,        <3> a C₃₋₈ cycloalkyl group which may be substituted by [1]        cyano group(s) or [2] C₁₋₈ alkyl group(s),        <4> a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(8B2),        <5> a C₁₋₈ alkoxy group which may be substituted by        substituent(s) selected from the group consisting of [1] a C₁₋₈        alkoxy group and [2] a C₃₋₈ cycloalkyl group,        <6> a C₁₋₈ alkylsulfonyl group,        <7> an oxo group,        <8> a cyano group,        <9> a C₁₋₈ alkanoyl group which may be substituted by one or        more R^(8B3),        <10> a C₃₋₈ cycloalkylcarbonyl group,        <11> a (C₁₋₈ alkyl)_(m8c)-aminosulfonyl group,        <12> a C₁₋₈ alkylsulfonyl (C₀₋₈ alkyl) amino group,        <13> a (C₁₋₈ alkyl)_(m8d)-amino group which may be substituted        by one or more R^(8B4),        <14> a hydroxy group, or        <15> a (C₁₋₈ alkyl)_(m8e)-aminocarbonyl group,    -   m8c: 0˜2,    -   m8d: 0˜2,    -   m8e: 0˜2,    -   R^(8B1): [1] a C₃₋₈ cycloalkyl group, [2] a hydroxy group, or        [3] C₁₋₈ alkoxy group which may be substituted by C₁₋₈ alkoxy        group(s),    -   R^(8B2): [1] a halogen atom, [2] a C₁₋₈ alkyl group, [3] an oxo        group, or [4] a hydroxy group,        -   R^(8B3): a (C₁₋₈ alkyl)_(m8f)-amino group,        -   m8f: 0˜2,        -   R^(8B4): [1] a C₃₋₈ cycloalkyl group, or [2] a hydroxy            group,    -   (5) a 5- to 14-membered heteroaryl group which may be        substituted by a C₁₋₈ alkyl group,    -   (6) a (C₁₋₈ alkyl)_(m8g)-aminocarbonyl group which may be        substituted by one or more R^(8C),        -   m8g: 0˜2,    -   R^(8C): [1] a hydroxy group, [2] a (C₁₋₈ alkyl)_(m8h)-amino        group which may be substituted by substituent(s) selected from        the group consisting of <1> a (C₁₋₈ alkyl)_(m8i)-aminosulfonyl        group and <2> a C₁₋₈ alkylsulfonyl group, or [3] a C₁₋₈        alkylsulfonyl group,        -   m8h: 0˜2,        -   m8i: 0˜2,    -   (7) a 4- to 10-membered heterocycloalkyl (C₀₋₈ alkyl)        aminocarbonyl group which may be substituted by oxo group(s),    -   (8) a 4- to 10-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by one        or more R^(8D),    -   R^(8D): [1] a C₁₋₈ alkyl group which may be substituted by one        or more R^(8D1), [2] a hydroxy group, or [3] a C₁₋₈        alkylsulfonyl group,    -   R^(8D1): [1] a hydroxy group, or [2] a C₁₋₈ alkoxy group,    -   (9) a hydroxycarbonyl group,    -   (10) a C₀₋₈ alkoxy (C₀₋₈ alkyl) aminocarbonyl group which may be        substituted by hydroxy group(s),    -   (11) a halogen atom,    -   (12) a (C₁₋₈ alkyl)_(m8j)-amino group which may be substituted        by 4- to 10-membered heterocycloalkyl group(s),        -   m8j: 0˜2,    -   (13) a hydroxyl group,    -   (14) a C₁₋₈ alkoxy group which may be substituted by one or more        R^(8E),    -   R^(8E):        <1> a hydroxy group,        <2> a C₁₋₈ alkoxycarbonyl group,        <3> a 4- to 10-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by one        or more R^(8E1),        <4> a (C₁₋₈ alkyl)_(m8k1)-amino group which may be substituted        by one or more R^(8E2),    -   m8k1: 0˜2,        <5> a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(8E3),        <6> a 5- to 14-membered heteroaryl group,        <7> a (C₁₋₈ alkyl)_(m8k2)-aminocarbonyl group which may be        substituted by one or more R^(8E6)    -   m8k2: 0˜2,        <8> a C₁₋₈ alkoxy group which may be substituted by one or more        R^(8E7),        <9> a C₁₋₈ alkylthio group,        <10> a C₁₋₈ alkylsulfinyl group, or        <11> a C₁₋₈ alkylsulfonyl group,    -   R^(8E1):        <1> a C₁₋₈ alkoxycarbonyl group,        <2> a C₁₋₈ alkanoyl group,        <3> a C₁₋₈ alkylsulfonyl group,        <4> a (C₁₋₈ alkyl)_(m8k3)-aminosulfonyl group    -   m8k3: 0˜2, or        <5> a 4- to 10-membered heterocycloalkyl group,    -   R^(8E2):        <1> a hydroxy group,        <2> a C₁₋₈ alkoxycarbonyl group,        <3> a C₃₋₈ cycloalkyl group which may be substituted by C₁₋₈        alkyl group(s) which may be substituted by hydroxy group(s),        <4> a C₁₋₈ alkanoyl group which may be substituted by        substituent(s) selected from the group consisting of [1] a (C₁₋₈        alkyl)_(m8k4)-amino group and [2] a halogen atom,    -   m8k4: 0˜2,        <5> a (C₁₋₈ alkyl)_(m8k5)-aminocarbonyl group,    -   m8k5: 0˜2,        <6> a C₁₋₈ alkylsulfonyl group,        <7> a 4- to 10-membered nitrogen-containing        heterocycloalkylsulfonyl group which may be substituted by C₁₋₈        alkyl group(s),        <8> a (C₁₋₈ alkyl)_(m8k6)-aminosulfonyl group,    -   m8k6: 0˜2, or    -   R^(8E3):        <1> a C₁₋₈ alkyl group which may be substituted by        substituent(s) selected from the group consisting of [1] a        hydroxy group and [2] a C₁₋₈ alkylcarbonyloxy group,        <2> a hydroxy group,        <3> a C₃₋₈ cycloalkyl group,        <4> a C₁₋₈ alkylsulfonyl group,        <5> a (C₁₋₈ alkyl)_(m8k8)-aminocarbonyl group,    -   m8k8: 0˜2,        <6> a C₁₋₈ alkanoyl group which may be substituted by hydroxy        group(s),        <7> an oxo group, or        <8> a 4- to 10-membered heterocycloalkyl group which may be        substituted by substituent(s) selected from the group consisting        of [1] a C₁₋₈ alkanoyl group, and [2] a C₁₋₈ alkylsulfonyl        group,    -   R^(8E6):        <1> a C₂₋₈ alkenylcarbonyloxy group,        <2> a hydroxy group,        <3> a cyano group,        <4> a (C₁₋₈ alkyl)_(m8k9)-amino group which may be substituted        by hydroxy group(s),    -   m8k9: 0˜2,        <5> a C₁₋₈ alkoxy group which may be substituted by hydroxy        group(s),        <6> a 4- to 10-membered heterocycloalkyl group which may be        substituted by C₁₋₈ alkyl group(s), or        <7> a 5- to 14-membered heteroaryl group,    -   R^(8E7):        <1> a hydroxy group, or        <2> a C₁₋₈ alkoxy group which may be substituted by hydroxy        group(s),    -   (15) a 4- to 10-membered heterocycloalkyloxy group which may be        substituted by one or more R^(8F):    -   R^(8F):        <1> a C₁₋₈ alkyl group which may be substituted by one or more        R^(8F1),        <2> a C₃₋₈ cycloalkyl group,        <3> a C₁₋₈ alkanoyl group which may be substituted by halogen        atom(s),        <4> a C₁₋₈ alkoxycarbonyl group,        <5> a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(8F2),        <6> a C₁₋₈ alkyl sulfonyl group, or        <7> a hydroxy group,    -   R^(8F1): [1] a hydroxy group, [2] a C₁₋₈ alkoxy group, or [3] a        halogen atom,    -   R^(8F2): [1] a 4- to 10-membered heterocycloalkyl group, [2] a        C₁₋₈ alkoxycarbonyl group, or [3] a C₁₋₈ alkylsulfonyl group,    -   (16) a 5- to 14-membered heteroaryloxy group,    -   (17) a (C₁₋₈ alkyl)_(m8l1)-aminosulfonyloxy group,        -   m8l1: 0˜2,    -   (18) a C₁₋₈ alkylthio group which may be substituted by (C₁₋₈        alkyl)_(m8l2)-amino group(s),        -   m8l2: 0˜2,    -   (19) a C₁₋₈ alkylsulfonyl group which may be substituted by one        or more R^(8G),    -   R^(8G): [1] a hydroxycarbonyl group, [2] a hydroxy group, or [3]        a (C₁₋₈ alkyl)_(m8l3)-amino group,        -   m8l3: 0˜2,    -   (20) a C₂₋₈ alkenyloxy group, and    -   (21) a C₁₋₈ alkylsulfonyloxy group which may be substituted by        halogen atom(s);    -   R⁹ is selected from the group consisting of:    -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group which may be substituted by one or more        R^(9A),    -   R^(9A): [1] a C₃₋₈ cycloalkyl group, [2] a 4- to 10-membered        heterocycloalkyl group which may be substituted by one or more        R^(9A1), [3] a hydroxy group, or [4] a C₁₋₈ alkoxy group,    -   R^(9A1): [1] a C₁₋₈ alkyl group, [2] a C₃₋₈ cycloalkyl group, or        [3] a 4- to 10-membered heterocycloalkyl group,    -   (3) a C₂₋₈ alkenyl group,    -   (4) a C₂₋₈ alkynyl group which may be substituted by one or more        R^(9C),    -   R^(9C): [1] a C₁₋₈ alkoxy group, [2] a (C₁₋₈ alkyl)_(m9b)-amino        group which may be substituted by C₆₋₁₀ aryl group(s), [3] a 4-        to 10-membered heterocycloalkyl group which may be substituted        by one or more R^(9C1), [4] a C₃₋₈ cycloalkyl group, [5] a        hydroxy group, or [6] a hydroxycarbonyl group,        -   m9b: 0˜2,    -   R^(9C1): [1] a C₃₋₈ cycloalkyl group, [2] a 4- to 10-membered        heterocycloalkyl group, or [3] an oxo group,    -   (5) a C₃₋₈ cycloalkyl group,    -   (6) a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more R^(9D),    -   R^(9D): [1] a C₁₋₈ alkyl group which may be substituted by 4- to        10-membered heterocycloalkyl group(s), [2] a C₃₋₈ cycloalkyl        group, [3] a 4- to 10-membered heterocycloalkyl group, or [4] a        C₁₋₆ alkylsulfonyl group,    -   (7) a C₆₋₁₀ aryl group which may be substituted by one or more        R^(9E),    -   R^(9E): [1] a halogen atom, [2] a hydroxy group, [3] a        hydroxycarbonyl group, or [4] a C₁₋₈ alkyl group which may be        substituted by hydroxy group(s),    -   (8) a 5- to 14-membered heteroaryl group which may be        substituted by C₁₋₈ alkyl group(s),    -   (9) a cyano group,    -   (10) a C₁₋₈ alkanoyl group,    -   (11) a 4- to 10-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by C₁₋₈        alkyl group(s),    -   (12) a halogen atom,    -   (13) a (C₁₋₈ alkyl)_(m9c)-amino group,        -   m9c: 0˜2,    -   (14) a C₁₋₈ alkylcarbonyl(C₀₋₈ alkyl)amino group which may be        substituted by (C_(1-s) alkyl)_(m9d)-amino group(s),        -   m9d: 0˜2,    -   (15) a C₁₋₈ alkylsulfonyl(C₀₋₈ alkyl)amino group,    -   (16) a (C₁₋₈ alkyl)_(m9e)-aminosulfonyl(C₀₋₈ alkyl)amino group,        -   m9e: 0˜2,    -   (17) a nitro group,    -   (18) a hydroxy group,    -   (19) a C₁₋₈ alkoxy group which may be substituted by one or more        R^(9G),    -   R^(9G): [1] a hydroxy group, [2] a hydroxycarbonyl group, [3] a        C₆₋₁₀ aryl group which may be substituted by C₁₋₈ alkoxy        group(s), [4] a (C₁₋₈ alkyl)_(m9g1)-amino group, [5] a C₁₋₈        alkoxy group which may be substituted by one or more R^(9G1), or        [6] a 5- to 14-membered heteroaryl group,        -   m9g1: 0˜2,    -   R^(9G1): [1] a C₁₋₈ alkoxy group, or [2] a hydroxycarbonyl        group,    -   (20) a 4- to 10-membered heterocycloalkyloxy group which may be        substituted by 4- to 10-membered heterocycloalkyl group(s),    -   (21) a C₁₋₈ alkylthio group which may be substituted by (C₁₋₈        alkyl)_(m9f)-amino group(s),        -   m9f: 0˜2,    -   (22) a C₁₋₈ alkylsulfonyl group which may be substituted by        (C₁₋₈ alkyl)_(m9g)-amino group(s),        -   m9g: 0˜2,    -   (23) a (C₁₋₈ alkyl)_(m9h)-aminosulfonyl group,        -   m9h: 0˜2, and    -   (24) a 4- to 10-membered nitrogen-containing        heterocycloalkylsulfonyl group which may be substituted by C₁₋₈        alkyl group(s);    -   R¹⁰ represents [1] a hydrogen atom, or [2] a 4- to 10-membered        heterocycloalkyl group which may be substituted by 4- to        10-membered heterocycloalkyl group(s)]. [6] A compound according        to claim 1, or salt or solvate thereof, which said compound is        selected from the group consisting of:

-   9-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   8-(4-cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   8-(1-isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   8-(2-tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

-   6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;    and

-   9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.    [7] A medicament comprising as an active ingredient the compound    according to any one of the above [1] to [5], or a salt or solvate    thereof.    [8] An ALK inhibitor comprising as an active ingredient the compound    according to any one of the above [1] to [5], or a salt or solvate    thereof.    [9] A pharmaceutical for the prophylaxis or treatment of cancer,    cancer metastasis, depression or cognitive function disorder,    comprising as an active ingredient the compound according to any one    of the above [1] to [5], or a salt or solvate thereof.    [10] A pharmaceutical composition comprising the compound according    to any one of the above [1] to [5], or a salt or solvate thereof and    a pharmaceutically acceptable carrier(s).    [11] A method of treating a patient suffering from the disease    including cancer, cancer metastasis, depression or cognitive    function disorder, comprising administering to the patient who is in    need of the treatment of the disease the compound described in any    one of the above [1] to [5], salt or solvate thereof in an effective    amount for the treatment of the disease.    [12] Use of the compound described in any one of the above [1] to    [5], salt or solvate thereof in the manufacture of a pharmaceutical.    [13] The use according to above [11] in the manufacture of a    pharmaceutical composition for the treatment or prophylaxis of the    disease of mammals including human, wherein the disease is related    with ALK activity.

Effect of the Invention

The compounds of the present invention or salts or salvates thereof havean excellent activity of inhibiting ALK, excellent stability inorganisms, and excellent solubility in water, and therefore are usefulas a prophylactic or therapeutic agent for proliferative disorders (inparticular, therapeutic agent). Further, the compounds of the presentinvention or salts salts or solvates thereof are useful as aprophylactic or therapeutic agent (in particular, therapeutic agent) forvarious diseases such as cancers including leukemia (acute myelogenousleukemia, chronic myelogenous leukemia, acute lymphatic leukemia,chronic lymphatic leukemia and the like), malignant lymphoma (Hodgkinlymphoma, non-Hodgkin lymphoma and the like), brain tumor,neuroblastoma, gliomatosis, thyroid cancer, myelodysplastic syndrome,head and neck cancer, esophageal cancer, stomach cancer, colon cancer,colorectal cancer, breast cancer, ovarian cancer, lung cancer,pancreatic cancer, liver cancer, gall bladder cancer, skin cancer,malignant melanoma, kidney cancer, renal pelvis-ureter cancer, bladdercancer, uterine cancer, testicle cancer, prostate cancer, and the like.Further, the compounds of the present invention are useful as aprophylactic or therapeutic agent (in particular, therapeutic agent) forinfiltration/metastasis of solid tumors. Still further, the compounds ofthe present invention are useful as a prophylactic or therapeutic agentfor other diseases that are related with ALK, for example, depression ora cognitive function disorder.

The method of the present invention comprises a step of administering apharmaceutically effective amount of the pharmaceutical compositioncomprising the compounds of the present invention or salts or solvatesthereof to a patient who is in need of such treatment or suffers fromsuch diseases or conditions.

Mode for Carrying Out the Invention

Hereinbelow, the compounds of the present invention, the method ofpreparing the same, and the pharmaceutical agent comprising the samewill be explained.

Definition

According to the present invention, the “halogen atom” means a fluorineatom, a chlorine atom, a bromine atom, an iodine atom and the like.According to the present invention, when the halogen atom is asubstituent group for an aromatic carbon ring, an aromatic heterocycleand the like, the preferred halogen atom includes a fluorine atom, achlorine atom and a bromine atom. According to the present invention,when the halogen atom is a substituent group for an alkyl group or agroup which comprises the alkyl as at least a part of the group (e.g.,alkoxy, alkenyl, unsaturated carbocycle, unsaturated heterocycle and thelike), the preferred halogen atom includes a fluorine atom.Specifically, examples thereof include a trifluoromethyl group, apentafluoroethyl group, a heptafluoropropyl group, a nonafluorobutylgroup, a trifluoromethoxy group, a pentafluoroethoxy group, aheptafluoropropoxy group, a nonafluorobutoxy group, a trifluoroacetylgroup, a pentafluoropropionyl group, a heptafluorobutyryl group and anonafluoropentanoyl group.

The “C₁₋₈ alkyl group” means a monovalent group which is derived byremoving any one of hydrogen atoms from a linear or branched aliphatichydrocarbon having 1 to 8 carbon atoms. Specifically, examples thereofinclude a methyl group, an ethyl group, an isopropyl group, a butylgroup, a n-butyl group, an isobutyl group, a sec-butyl group, a t-butylgroup, a pentyl group, an isopentyl group, a 2,3-dimethyl propyl group,a hexyl group, a 2,3-dimethyl hexyl group, a 1,1-dimethyl pentyl group,a heptyl group and an octyl group. Preferably, it is a C₁₋₆ alkyl group,more preferably a C₁₋₅ alkyl group, still more preferably a C₁₋₄ alkylgroup, and still even more preferably a C₁₋₃ alkyl group.

The “C₁₋₈ alkyl group which may be substituted” means an unsubstitutedC₁₋₈ alkyl group or a C₁₋₈ alkyl group of which at least one hydrogenatom on the alkyl group is substituted by a defined substituent(s). Whentwo or more substituent groups are present, each substituent group canbe the same or different from each other. In addition, the alkyl groupmay be substituted by a cyclic substituent group through a spiro bond.Preferably, it is a C₁₋₈ alkyl group which may be substituted by 1 to 3substituent(s). More preferably, it is 1 to 3 substituent(s) for C₁₋₆alkyl group and a C₁₋₄ alkyl group, and 1 to 2 substituent(s) for a C₁₋₃alkyl group.

The “C₂₋₈ alkenyl group” means a monovalent group wherein at least onedouble bond (two adjacent SP2 carbon atoms) is comprised in a linear orbranched aliphatic hydrocarbon group having 1 to 8 carbon atoms.Specific examples of the C₂₋₈ alkenyl group include a vinyl group, anallyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group,a 2-butenyl group (including both cis and trans), a 3-butenyl group, apentenyl group and a hexenyl group. Preferably, it is a C₂₋₆ alkenylgroup, more preferably a C₂₋₅ alkenyl group, still more preferably aC₂₋₄ alkenyl group, and still even more preferably a C₂₋₃ alkenyl group.

The “C₂₋₈ alkenyl group which may be substituted” means theunsubstituted C₂₋₈ alkenyl group described above or a C₂₋₈ alkenyl groupof which at least one hydrogen atom on the alkenyl group is substitutedby a defined substituent(s). When two or more substituent groups arepresent, each substituent group can be the same or different from eachother. In addition, the single-bonded carbon atom may be substituted bya cyclic substituent group through a spiro bond. Preferably, it is aC₂₋₈ alkenyl group which may be substituted by 1 to 3 substituent(s).More preferably, it is 1 to 3 substituent(s) for a C₂₋₆ alkenyl groupand a C₂₋₄ alkenyl group, 1 to 2 substituent(s) for a C₂₋₃ alkenylgroup.

The “C₂₋₈ alkynyl group” means a monovalent group wherein at least onetriple bond (two adjacent SP carbon atoms) is comprised in a linear orbranched aliphatic hydrocarbon group having 1 to 8 carbon atoms.Specific examples of the C₂₋₈ alkynyl group include an ethynyl group, a1-propynyl group, a propargyl group and a 3-butynyl group. Preferably,it is a C₂₋₆ alkynyl group, more preferably a C₂₋₅ alkynyl group, stillmore preferably a C₂₋₄ alkynyl group, and still even more preferably aC₂₋₃ alkynyl group.

The “C₂₋₈ alkynyl group which may be substituted” means theunsubstituted C₂₋₈ alkynyl group described above or a C₂₋₈ alkynyl groupof which at least one hydrogen atom on the alkynyl group is substitutedby a defined substituent(s). When two or more substituent groups arepresent, each substituent group can be the same or different from eachother. In addition, the single-bonded carbon atom may be substituted bya cyclic substituent group through a spiro bond. Preferably, it is aC₂₋₈ alkynyl group which may be substituted by 1 to 3 substituent(s).More preferably, it is 1 to 3 substituent(s) for a C₂₋₆ alkynyl groupand a C₂₋₄ alkynyl group, and 1 to 2 substituent(s) for C₂₋₃ alkynylgroup.

The “C₃₋₈ cycloalkyl group” means an aliphatic hydrocarbon group incyclic form. Preferably, it includes a C₃₋₆ cycloalkyl group.Specifically, examples thereof include a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group anda cyclooctyl group. Preferably, it is a C₃₋₆ cycloalkyl group.

The “C₃₋₈ cycloalkyl group which may be substituted” means theunsubstituted C₃₋₈ cycloalkyl group described above or a C₃₋₈ cycloalkylgroup of which at least one hydrogen atom is substituted by a definedsubstituent group(s). When two or more substituent groups are present,each substituent group can be the same or different from each other. Inaddition, the single-bonded carbon atom may be substituted by a cyclicsubstituent group through a spiro bond. Preferably, it is a C₃₋₈cycloalkyl group which may be substituted by 1 to 3 substituent(s).

The “4- to 10-membered heterocycloalkyl group” means a saturated orpartially unsaturated heterocyclic group which consists of 4 to 10ring-constituting atoms and comprises 1 to 3 hetero atoms that areselected from O, S and N. The heterocycloalkyl group can be amonocyclic, a bicyclic or a spirocyclic type heterocycloalkyl group.Specifically, examples thereof include an oxetanyl group, atetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydropyranylgroup, a pyrrolidino group, a pyrrolidinyl group, a piperidino group, apiperidinyl group, a piperazino group, a piperazinyl group, a morpholinogroup, a morpholinyl group, a tetrahydrothiopyranyl group, athiomorpholino group, an imidazolidinyl group, a 1,3-dioxolanyl group, atetrahydropyranyl group, a 1,3-dioxanyl group, a1,2,3,6-tetrahydropyridinyl group, a 1,4-Dioxa-8-aza-spiro[4.5]decanylgroup, and a 1-oxa-8-aza-spiro[4.5]decanyl group. Preferably, it is a 4-to 8-membered heterocycloalkyl group, more preferably, 4- to 6-memberedheterocycloalkyl group.

The “4- to 10-membered heterocycloalkyl group which may be substituted”means the unsubstituted 4- to 10-membered heterocycloalkyl groupdescribed above or a 4- to 10-membered heterocycloalkyl group of whichat least one hydrogen atom on the heterocycloalkyl group is substitutedby a defined substituent(s). When two or more substituent groups arepresent, each substituent group can be the same or different from eachother. In addition, the alkyl group may be substituted by a cyclicsubstituent group through a spiro bond. Preferably, it is a 4- to10-membered heterocycloalkyl group which may be substituted by 1 to 4substituent(s). More preferably, it is 1 to 4 substituent(s) for a 4- to8-membered heterocycloalkyl group, and 1 to 3 substituent(s) for a 4- to6-membered heterocycloalkyl group. When the substituent is an oxo group,2 oxo group can combine with the same sulfur atom. When the salt isformed, 2 alkyl group can combine with the same nitrogen atom.

The “C₆₋₁₀ aryl group” means a monovalent aromatic hydrocarbon ring.Specific examples of the C₆₋₁₀ aryl group include a phenyl group, a1-naphthyl group and a 2-naphthyl group. Preferably, it is a C₆ arylgroup or a C₁₀ aryl group.

The “C₆₋₁₀ aryl group which may be substituted” means the unsubstitutedC₆₋₁₀ aryl group described above or a C₆₋₁₀ aryl group of which at leastone hydrogen atom is substituted by a defined substituent group(s). Whentwo or more substituent groups are present, each substituent group canbe the same or different from each other. Preferably, it is a C₆₋₁₀ arylgroup which may be substituted by 1 to 3 substituent(s).

The “5- to 14-membered heteroaryl group” means an aromatic cyclic groupcomprising one or more hetero atoms among 5 to 14 ring-constitutingatoms. The cycle can be a monocyclic or bicyclic heteroaryl group fusedto a benzene ring or a monocyclic heteroaryl ring. Specific examplesthereof include a furyl group, a thienyl group, a pyrrolyl group, animidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolylgroup, an oxazolyl group, an isooxazolyl group, an oxadiazolyl group, athiadiazolyl group, a triazolyl group, a tetrazolyl group, a pyridylgroup, a pyrimidyl group, a pyridazinyl group, a pyrazinyl group, atriazinyl group, a benzofuranyl group, a benzothienyl group, abenzothiadiazolyl group, a benzothiazolyl group, a benzoxazolyl group, abenzoxadiazolyl group, a benzoimidazolyl group, an indolyl group, anisoindolyl group, an indazolyl group, a quinolyl group, an isoquinolylgroup, a cinnolinyl group, a quinazolinyl group, a quinoxalinyl group, abenzodioxolyl group, an indolizinyl group, an imidazopyridyl group andthe like. Preferably, it is a 5- to 6-membered heteroaryl group.

The “5- to 14-membered heteroaryl group which may be substituted” meansthe unsubstituted 5- to 14-membered ring heteroaryl group describedabove or a 5- to 14-membered ring heteroaryl group of which at least onehydrogen atom on the heteroaryl group is substituted by a definedsubstituent(s). When two or more substituent groups are present, eachsubstituent group can be the same or different from each other.Preferably, it is a 5- to 14-membered heteroaryl group which may besubstituted by 1 to 3 substituent(s). More preferably, it is 1 to 3substituent(s) or 1 to 2 substituent(s) for a 5- to 6-memberedheteroaryl group.

The “C₁₋₈ alkanoyl group” means a C₁₋₈ alkyl-C(O)— group, and the C₁₋₈alkyl group is described above. Specifically, examples thereof includeacetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyland a hexanoyl group. Preferably, it is a C₁₋₆ alkanoyl group, and morepreferably a C₁₋₃ alkanoyl group.

The “C₁₋₈ alkanoyl group which may be substituted” means theunsubstituted C₁₋₈ alkanoyl group described above or a C₁₋₈ alkanoylgroup of which at least one hydrogen atom on the alkanoyl group issubstituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. Preferably, it is a C₁₋₈ alkanoyl group which may besubstituted by 1 to 3 substituent(s). More preferably, it is 1 to 2substituent(s) for a C₁₋₆ alkanoyl group and a C₁₋₃ alkanoyl group.

The “C₃₋₈ cycloalkylcarbonyl group” means a C₃₋₈ cycloalkyl-C(O)— group,and the C₃₋₈ cycloalkyl group is described above. Specifically, examplesthereof include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group,a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, acycloheptylcarbonyl group and a cyclooctylcarbonyl group.

The “4- to 10-membered heterocycloalkylcarbonyl group” means a 4- to10-membered heterocycloalkyl-CO— group, and the 4- to 10-memberedheterocycloalkyl is described above.

The “4- to 10-membered heterocycloalkylcarbonyl group which may besubstituted” means the unsubstituted 4- to 10-memberedheterocycloalkylcarbonyl group described above or a 4- to 10-memberedheterocycloalkylcarbonyl group in which at least one hydrogen atom ofthe heterocycloalkyl moiety is substituted by a defined substituent(s).When two or more substituent groups are present, each substituent groupcan be the same or different from each other. In addition, theheterocycloalkyl moiety may be substituted by a cyclic substituent groupthrough a spiro bond. Preferably, it is a 4- to 10-memberedheterocycloalkylcarbonyl group which may be substituted by 1 to 3substituent(s).

The “aminocarbonyl group which may be substituted” means anunsubstituted aminocarbonyl group or an aminocarbonyl group in which oneor two hydrogen atoms on the nitrogen atom are substituted by a definedsubstituent(s). When two substituent groups are present, eachsubstituent group can be the same or different from each other.

The “C₃₋₈ cycloalkyl (C₀₋₈ alkyl) aminocarbonyloxy group” means a C₃₋₈cycloalkyl-NHC(O)O— group or a C₃₋₈ cycloalkyl-N(C₁₋₈ alkyl) C(O)O—group, and the C₃₋₈ cycloalkyl group is described above. Specifically,examples thereof include a cyclopropylaminocarbonyloxy group, acyclobutylaminocarbonyloxy group, a cyclopentylaminocarbonyloxy group, acyclohexylaminocarbonyloxy group, acyclopropyl(N-methyl)aminocarbonyloxy group, and acyclobutyl(N-methyl)aminocarbonyloxy group.

The “(C₁₋₈ alkyl)_(x)-aminocarbonyl group”, wherein x is a symboldefined in claims, means a NH₂C(O)— group, a (C₁₋₈ alkyl)NH—C(O)— group,or a (C₁₋₈ alkyl)₂N—C(O)— group. Specifically, examples thereof includea N-methyl-aminocarbonyl group, N-ethyl-aminocarbonyl group,N-n-buthyl-aminocarbonyl group, a N,N-dimethyl-aminocarbonyl group.

The “(C₁₋₈ alkyl)_(x)-aminocarbonyl group which may be substituted”means an unsubstituted (C₁₋₈ alkyl)_(x)-aminocarbonyl group describedabove or an (C₁₋₈ alkyl)_(x)-aminocarbonyl group in which at least onehydrogen atom on the nitrogen atom or the alkyl moiety are substitutedby a defined substituent(s). When plural substituent groups are present,each substituent group can be the same or different from each other.

The “C₆₋₁₀ aryl(C₀₋₈ alkyl)aminocarbonyl group” means a C₆₋₁₀aryl-NHC(O)— group, or a C₆₋₁₀ aryl-N(C₁₋₈ alkyl)-C(O)— group.Specifically, examples thereof include a phenyl-NHC(O)— group, or aphenyl-(N-methyl)-aminocarbonyl group, wherein the C₆₋₁₀ aryl group andC₁₋₈ alkyl are described above. Specifically, examples thereof include aphenylaminocarbonylamino group and a phenylaminocarbonyl(N-methyl)aminogroup.

The “4- to 10-membered nitrogen-containing heterocycloalkylcarbonylgroup” means a carbonyl group to which a 4- to 10-memberednitrogen-containing heterocycloalkyl group is bonded. Herein, the 4- to10-membered nitrogen-containing heterocycloalkyl group (i.e., 4- to10-membered heterocycloalkyl group comprising a nitrogen atom(s)) meansa heterocycloalkyl group which consists of 4 to 10 ring-constitutingatoms and comprises at least one nitrogen atom as a hetero atom.Preferably, it is bonded to the carbonyl group via a nitrogen atom thatis comprised in the heterocycloalkyl ring. Specific examples of the 4-to 10-membered nitrogen-containing heterocycloalkyl group include apyrrolidinyl group, an imidazolidinnyl group, a morpholino group, athiomorphorino group, a piperazino group and a piperidino group. As forthe 4- to 10-membered nitrogen-containing heterocycloalkylcarbonylgroup, examples thereof include a pyrrolidinocarbonyl group, apiperidinocarbonyl group, a piperazinocarbonyl group and amorpholinocarbonyl group.

The “4- to 10-membered nitrogen-containing heterocycloalkylcarbonylgroup, which may be substituted” means the unsubstituted 4- to10-membered nitrogen-containing heterocycloalkylcarbonyl group asdescribed above or a 4- to 10-membered heterocycloalkylcarbonyl group inwhich at least one hydrogen atom of the heterocycloalkyl moiety issubstituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. In addition, the heterocycloalkyl moiety may besubstituted by a cyclic substituent group through a spiro bond.Preferably, it is a 4- to 10-membered nitrogen-containingheterocycloalkylcarbonyl group which may be substituted by 1 to 3substituent(s).

The “4- to 10-membered heterocycloalkyl (C₀₋₈ alkyl) aminocarbonylgroup” means 4- to 10-membered heterocycloalkyl NHC(O)— group, or a 4-to 10-membered heterocycloalkyl N(C₁₋₈ alkyl)-C(O)— group. Specifically,examples thereof include a oxetan-3-yl amide group, and a(1,1-dioxo-tetrahydro-thiophen-3-yl)-amide group.

The “4- to 10-membered heterocycloalkyl (C₀₋₈ alkyl) aminocarbonyl groupwhich may be substituted by one or more oxo groups” means theunsubstituted 4- to 10-membered heterocycloalkylaminocarbonyl groupdescribed above or the 4- to 10-membered heterocycloalkylaminocarbonylgroup in which the heterocycloalkyl moiety is substituted by at leastone oxo group.

The “C₆₋₁₀ arylsulfonyl group” means a C₆₋₁₀ aryl-S(O)₂— group and theC₆₋₁₀ aryl group is described above. Specifically, examples thereofinclude a phenylsulfonyl group.

The “5- to 14-membered heteroarylsulfonyl group” means a 5- to14-membered heteroaryl-S(O)₂— group, and the 5- to 14-memberedheteroaryl is described above. Specifically, examples thereof include aimidazol-sulfonyl group.

The “(C₁₋₈ alkyl)_(x)-amino group”, wherein x is a symbol defined inclaims, means an amino group, a NH(C₁₋₈ alkyl) group, or a N(C₁₋₈alkyl)₂- group. Specifically, examples thereof include amino,methylamino, ethylamino, butylamino, isopropylamino, dimethylamino anddiethylamino. Preferably, it is a C₁₋₃ alkylamino group.

The “(C₁₋₈ alkyl)_(x)-amino group which may be substituted” means anunsubstituted (C₁₋₈ alkyl)_(x)-amino group or an amino group in whichone or two hydrogen atoms on the nitrogen atom or the alkyl moiety aresubstituted by a defined substituent(s). When two substituent groups arepresent, each substituent group can be the same or different from eachother.

The “C₁₋₈ alkylcarbonyl (C₀₋₈ alkyl) amino group” means a C₁₋₈alkyl-C(O)—NH— group or a C₁₋₈ alkyl-C(O)—N(C₁₋₈ alkyl)- group, and theC₁₋₈ alkyl is described above. Specifically, examples thereof include amethylcarbonylamino group, an ethylcarbonylamino group, apropylcarbonylamino group and a butylcarbonylamino group.

The “C₁₋₈ alkylcarbonyl (C₀₋₈ alkyl) amino group which may besubstituted” means the unsubstituted C₁₋₈ alkylcarbonyl (C₀₋₈ alkyl)amino group described above or the C₁₋₈ alkylcarbonyl (C₀₋₈ alkyl) aminogroup in which at least one hydrogen atoms of the terminal alkyl moietyis substituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. In addition, the alkyl moiety may be substituted by acyclic substituent group through a spiro bond. Preferably, it is a C₁₋₈alkylcarbonyl (C₀₋₈ alkyl) amino group which may be substituted by 1 to3 substituent(s).

The “C₆₋₁₀ arylcarbonyl (C₀₋₈ alkyl) amino group” means a C₆₋₁₀aryl-C(O)—NH— group or a C₆₋₁₀ aryl-C(O)—N(C₁₋₈ alkyl)- group and theC₆₋₁₀ aryl group and the C₁₋₈ alkyl group are described above.Specifically, examples thereof include a phenylcarbonylamino group.

The “C₆₋₁₀ arylcarbonyl (C₀₋₈ alkyl) amino group which may besubstituted” means the unsubstituted C₆₋₁₀ arylcarbonyl (C₀₋₈ alkyl)amino group described above or the C₆₋₁₀ arylcarbonyl (C₀₋₈ alkyl) aminogroup in which at least one hydrogen atoms of the aryl moiety issubstituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. Preferably, it is a C₆₋₁₀ arylcarbonyl (C₀₋₈ alkyl)amino group which may be substituted by 1 to 3 substituent(s).

The “(C₁₋₈ alkyl)_(x)-aminocarbonyl (C₀₋₈ alkyl) amino group”, wherein xis a symbol defined in claims, means a NH₂C(O)NH— group, a (C₁₋₈alkyl)NHC(O)NH— group, a NH₂C(O)N(C₁₋₈ alkyl)- group, or a (C₁₋₈alkyl)NHC(O)N(C₁₋₈ alkyl)- group, and the C₁₋₈ alkyl is described above.Specifically, examples thereof include aminocarbonyl-(N-methyl)amino,and (N-methyl)aminocarbonyl-(N′-methyl)amino.

The “(C₁₋₈ alkyl)_(x)-aminocarbonyl (C₀₋₈ alkyl) amino group which maybe substituted” means an unsubstituted (C₁₋₈ alkyl)_(x)-aminocarbonyl(C₀₋₈ alkyl) amino group, or a (C₁₋₈ alkyl)_(x)-aminocarbonyl (C₀₋₈alkyl) amino group in which at least one hydrogen atom on the nitrogenatom or the alkyl moiety is substituted by a defined substituent.Preferably, it is a (C₁₋₈ alkyl)_(x)-aminocarbonyl (C₀₋₈ alkyl) aminogroup which may be substituted by a phenyl group.

The “C₁₋₈ alkylsulfonylamino group” means a C₁₋₈ alkyl-S(O)₂—NH— groupand the C₁₋₆ alkyl group is described above. Specifically, examplesthereof include a methylsulfonylamino group and an ethylsulfonylaminogroup.

The “(C₁₋₈ alkyl)_(x)-aminosulfonyl(C₀₋₈ alkyl)amino group”, wherein xis a symbol defined in claims, means a NH₂S(O)₂NH— group, a NH(C₁₋₈alkyl)-S(O)₂NH— group, or a N(C₁₋₈ alkyl)₂-S(O)₂NH— group, a NH₂S(O)₂N(C₁₋₈ alkyl)- group, a NH(C₁₋₈ alkyl)-S(O)₂ (C₁₋₈ alkyl)N— group, or aN(C₁₋₈ alkyl)₂-S(O)₂ (C₁₋₈ alkyl) N— group, and the C₁₋₈ alkyl group isdescribed above. Specifically, examples thereof include amethylamino-sulfonylamino group and a dimethylamino-sulfonylamino group.

The “C₁₋₈ alkoxy group” means a C₁₋₈ alkyl-O— group. Specifically,examples thereof include a methoxy group, an ethoxy group, a 1-propoxygroup, a 2-propoxy group, a n-butoxy group, an i-butoxy group, asec-butoxy group, a t-butoxy group, a 1-pentyloxy group, a 2-pentyloxygroup, a 3-pentyloxy group, a 2-methyl-1-butyloxy group, a3-methyl-1-butyloxy group, a 2-methyl-2-butyloxy group, a3-methyl-2-butyloxy group, a 2,2-dimethyl-1-propyloxy group, a1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a2-methyl-1-pentyloxy group, a 3-methyl-1-pentyloxy group, a4-methyl-1-pentyloxy group, a 2-methyl-2-pentyloxy group, a3-methyl-2-pentyloxy group, a 4-methyl-2-pentyloxy group, a2-methyl-3-pentyloxy group, a 3-methyl-3-pentyloxy group, a2,3-dimethyl-1-butyloxy group, a 3,3-dimethyl-1-butyloxy group, a2,2-dimethyl-1-butyloxy group, a 2-ethyl-1-butyloxy group, a3,3-dimethyl-2-butyloxy group, a 2,3-dimethyl-2-butyloxy group and a1-methyl-cyclopropylmethoxy group. Preferably, it is a C₁₋₆ alkoxygroup, more preferably a C₁₋₅ alkoxy group, still more preferably a C₁₋₄alkoxy group, and still even more preferably a C₁₋₃ alkoxy group.

The “C₁₋₈ alkoxy group which may be substituted” means an unsubstitutedC₁₋₈ alkoxy group or a C₁₋₈ alkoxy group in which at least one hydrogenatom of the alkyl moiety is substituted by a defined substituent(s).When two or more substituent groups are present, each substituent groupcan be the same or different from each other. In addition, the alkylmoiety may be substituted by a cyclic substituent group through a spirobond. Preferably, it is a C₁₋₈ alkoxy group which may be substituted by1 to 3 substituent(s). More preferably, it is 1 to 3 substituent(s) forC₁₋₆ alkoxy group and a C₁₋₄ alkoxy group, and 1 to 2 substituent(s) fora C₁₋₃ alkoxy group.

The “C₁₋₈ alkoxycarbonyl group” means a C₁₋₈ alkyl-O—C(O)— group and theC₁₋₈ alkyl group is described above. Specifically, examples thereofinclude a methoxycarbonyl group, an ethoxycarbonyl group, an-propoxycarbonyl group and an i-propoxycarbonyl group. Preferably, itis a C₁₋₆ alkoxycarbonyl group, and more preferably a C₁₋₃alkoxycarbonyl group.

The “C₁₋₈ alkoxycarbonyl group which may be substituted” means theunsubstituted C₁₋₈ alkoxycarbonyl group described above or a C₁₋₈alkoxycarbonyl group of which at least one hydrogen atom is substitutedby a defined substituent(s). When two or more substituent groups arepresent, each substituent group can be the same or different from eachother. In addition, the alkyl moiety of the alkoxycarbonyl group may besubstituted by a cyclic substituent group through a spiro bond.Preferably, it is a C₁₋₈ alkoxycarbonyl group which may be substitutedby 1 to 3 substituent(s).

The “C₀₋₈ alkoxy (C₀₋₈ alkyl) aminocarbonyl group” means a HO—NH—C(O)—group, a C₁₋₈ alkyl-NH—C(O)— group, a HO—N(C₁₋₈ alkyl)-C(O)— group, or aC₁₋₈ alkyl-N(C₁₋₈ alkyl)-C(O)— group, and has a C₁₋₈ alkoxy group or aC₁₋₈ alkyl group as described above. Specifically, examples thereofinclude a methoxyaminocarbonyl group, an ethoxyaminocarbonyl group, an-propoxyaminocarbonyl group and an i-propoxyaminocarbonyl group.Preferably, it is a C₁₋₆ alkoxyaminocarbonyl group, and more preferablya C₁₋₃ alkoxyaminocarbonyl group.

The “C₀₋₈ alkoxy (C₀₋₈ alkyl) aminocarbonyl group which may besubstituted” means the unsubstituted hydroxyaminocarbonyl groupdescribed above, or a C₁₋₈ alkoxyaminocarbonyl group, a hydroxy (C₁₋₈alkyl) aminocarbonyl group or a C₁₋₈ alkoxy (C₁₋₈ alkyl) aminocarbonylgroup, wherein at least one hydrogen atom of the alkyl moiety issubstituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. In addition, the alkyl moiety may be substituted by acyclic substituent group through a spiro bond. Preferably, it is a C₁₋₈alkoxy aminocarbonyl group which may be substituted by 1 to 3substituent(s).

The “4- to 10-membered heterocycloalkyloxy group” means a 4- to10-membered heterocycloalkyl-O— group, and the 4- to 10-memberedheterocycloalkyl is described above.

The “4- to 10-membered heterocycloalkyloxy group which may besubstituted” means the unsubstituted 4- to 10-memberedheterocycloalkyloxy group described above or a 4- to 10-memberedheterocycloalkyloxy group in which at least one hydrogen atom of theheterocycloalkyl moiety is substituted by a defined substituent(s). Whentwo or more substituent groups are present, each substituent group canbe the same or different from each other. In addition, theheterocycloalkyl moiety may be substituted by a cyclic substituent groupthrough a spiro bond. Preferably, it is a 4- to 10-memberedheterocycloalkyloxy group which may be substituted by 1 to 3substituent(s).

The “C₆₋₁₀ aryloxy group” means a C₆₋₁₀ aryl-O— group, and the C₆₋₁₀aryl group is described above.

The “5- to 14-membered heteroaryloxy group” means a 5- to 14-memberedheteroaryl-O— group, and the 5- to 14-membered heteroaryl is describedabove. Specifically, examples thereof include a pyrimidinyloxy group.

The “C₁₋₈ alkylcarbonyloxy group” means a C₁₋₈ alkyl-C(O)—O— group, andthe C₁₋₈ alkyl is described above. Specifically, examples thereofinclude a methylcarbonyloxy group, an ethylcarbonyloxy group and apropylcarbonyloxy group.

The “C₂₋₈ alkenylcarbonyloxy group” means a C₂₋₈ alkenyl-C(O)—O— group,and the C₂₋₈ alkenyl is described above. Specifically, examples thereofinclude a 2-methyl-2-butenoyloxy group.

The “4- to 10-membered heterocycloalkylcarbonyloxy group” means a 4- to10-membered heterocycloalkyl-C(O)—O— group, and the 4- to 10-memberedheterocycloalkyl is described above.

The “(C₁₋₈ alkyl)_(x)-aminocarbonyloxy group”, wherein x is a symboldefined in claims, means a NH₂C(O)—O— group, a NH(C₁₋₈ alkyl)-C(O)—O—group, or a N(C₁₋₈ alkyl)₂—C(O)—O— group. Specifically, examples thereofinclude a methylamino-carbonyloxy group, an ethylamino-carbonyloxy groupand a propylamino-carbonyloxy group.

The “(C₁₋₈ alkyl)_(x)-aminocarbonyloxy group which may be substituted”means an unsubstituted (C₁₋₈ alkyl)_(x)-aminocarbonyloxy group or a(C₁₋₈ alkyl)_(x)-aminocarbonyloxy group group in which one or twohydrogen atoms on the nitrogen atom or the alkyl moiety are substitutedby a defined substituent(s). When two substituent groups are present,each substituent group can be the same or different from each other.

The “4- to 10-membered nitrogen-containing heterocycloalkylsulfonylgroup” means the 4- to 10-membered nitrogen-containingheterocycloalkyl-S(O)₂— group described above. Specifically, examplesthereof include a morphorino-sulfonyl group.

The “4- to 10-membered nitrogen-containing heterocycloalkylsulfonylgroup which may be substituted” means the unsubstituted 4- to10-membered nitrogen-containing heterocycloalkylsulfonyl group describedabove or the 4- to 10-membered nitrogen-containingheterocycloalkylsulfonyloxy group in which at least one hydrogen atom ofthe 4- to 10-membered nitrogen-containing heterocycloalkyl moiety issubstituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. Preferably, it is a 4- to 10-memberednitrogen-containing heterocycloalkylsulfonyl which may be substituted by1 to 3 substituent(s).

The “4- to 10-membered nitrogen-containing heterocycloalkylsulfonyloxygroup” means the 4- to 10-membered nitrogen-containingheterocycloalkyl-S(O)₂—O— group described above. Specifically, examplesthereof include a morphorino-sulfonyloxy group and apiperadino-sulfonyloxy group.

The “4- to 10-membered nitrogen-containing heterocycloalkylsulfonyloxygroup which may be substituted” means the unsubstituted 4- to10-membered nitrogen-containing heterocycloalkylsulfonyloxy groupdescribed above or the 4- to 10-membered nitrogen-containingheterocycloalkylsulfonyloxy group in which at least one hydrogen atom ofthe 4- to 10-membered nitrogen-containing heterocycloalkyl moiety issubstituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. Preferably, it is a 4- to 10-memberednitrogen-containing heterocycloalkylsulfonyloxy which may be substitutedby 1 to 3 substituent(s).

The “C₁₋₈ alkylsulfonyloxy group” means a C₁₋₈ alkyl-S(O)₂—O— group, andthe C₁₋₈ alkyl is described above.

The “C₁₋₈ alkylsulfonyloxy group which may be substituted” means theunsubstituted C₁₋₈ alkylsulfonyloxy group described above or a C₁₋₈alkylsulfonyloxy group in which at least one hydrogen atom of the alkylmoiety is substituted by a defined substituent(s). When two or moresubstituent groups are present, each substituent group can be the sameor different from each other. In addition, the alkyl moiety may besubstituted by a cyclic substituent group through a spiro bond.Preferably, it is a C₁₋₈ alkylsulfonyloxy group which may be substitutedby 1 to 3 substituent(s). Specifically, examples thereof include atrifluoromethylsulfonyloxy group.

The “(C₁₋₈ alkyl)_(x)-aminosulfonyloxy group” wherein x is a symboldefined in claims, means a NH₂S(O)₂— group, a N(C₁₋₈ alkyl)S(O)₂— group,or a N(C₁₋₈ alkyl)₂S(O)₂— group. Specifically, examples thereof includea N-methylaminosulfonyloxy group.

The “C₁₋₈ alkylthio group” means a C₁₋₈ alkyl-S— group, and the C₁₋₈alkyl group is described above. Examples thereof include methylthio,ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio,i-butylthio, t-butylthio, n-pentylthio, 3-methylbutylthio,2-methylbutylthio, 1-methylbutylthio, 1-ethylpropylthio, n-hexylthio,4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio,1-methylpentylthio, 3-ethylbutylthio, and 2-ethylbutylthio and the like.Preferably, it is a C₁₋₆ alkylthio group, and more preferably a C₁₋₃alkylthio group.

The “C₁₋₈ alkylthio group which may be substituted” means anunsubstituted C₁₋₈ alkylthio group or a C₁₋₈ alkylthio group in which atleast one hydrogen atom of the alkyl moiety is substituted by a definedsubstituent(s). When two or more substituent groups are present, eachsubstituent group can be the same or different from each other. Inaddition, the alkyl moiety may be substituted by a cyclic substituentgroup through a spiro bond. Preferably, it is a C₁₋₈ alkylthio groupwhich may be substituted by 1 to 3 substituent(s).

The “C₁₋₈ alkylsulfonyl group” means a C₁₋₈ alkyl-S(O)₂— group, and theC₁₋₈ alkyl group is described above. Specifically, examples thereofinclude a methylsulfonyl group, an ethylsulfonyl group and an-propylsulfonyl group. Preferably, it is a C₁₋₆ alkylsulfonyl group,and more preferably a C₁₋₃ alkylsulfonyl group.

The “C₁₋₈ alkylsulfinyl group” means a C₁₋₈ alkyl-S(O)— group, and theC₁₋₈ alkyl group is described above. Specifically, examples thereofinclude a methylsulfinyl group, an ethylsulfinyl group and an-propylsulfinyl group. Preferably, it is a C₁₋₆ alkylsulfinyl group,and more preferably a C₁₋₃ alkylsulfinyl group.

The “C₁₋₈ alkylsulfonyl group which may be substituted” means theunsubstituted C₁₋₈ alkylsulfonyl group described above or a C₁₋₈alkylsulfonyl group in which at least one hydrogen atom of the alkylmoiety is substituted by a defined substituent(s). When two or moresubstituent groups are present, each substituent group can be the sameor different from each other. Preferably, it is a C₁₋₈ alkylsulfonylgroup which may be substituted by 1 to 3 substituent(s).

The “C₁₋₈ alkylsulfinyl group which may be substituted” means theunsubstituted C₁₋₈ alkylsulfinyl group described above or a C₁₋₈alkylsulfinyl group in which at least one hydrogen atom of the alkylmoiety is substituted by a defined substituent(s). When two or moresubstituent groups are present, each substituent group can be the sameor different from each other. Preferably, it is a C₁₋₈ alkylsulfinylgroup which may be substituted by 1 to 3 substituent(s).

The “4- to 10-membered heterocycloalkylsulfonyl group” means a 4- to10-membered heterocycloalkyl-S(O)₂— group, and the 4- to 10-memberedheterocycloalkyl is described above.

The “4- to 10-membered heterocycloalkylsulfonyl group which may besubstituted” means the unsubstituted 4- to 10-memberedheterocycloalkylsulfonyl group described above or a 4- to 10-memberedheterocycloalkylsulfonyl group in which at least one hydrogen atom ofthe heterocycloalkyl moiety is substituted by a defined substituent(s).When two or more substituent groups are present, each substituent groupcan be the same or different from each other. In addition, theheterocycloalkyl moiety may be substituted by a cyclic substituent groupthrough a spiro bond. Preferably, it is a 4- to 10-memberedheterocycloalkylsulfonyl group which may be substituted by 1 to 3substituent(s).

The “(C₁₋₈ alkyl)_(x)-aminosulfonyl group”, wherein x is a symboldefined in claims, means a NH₂—S(O)₂— group, a C₁₋₈ alkylamino-S(O)₂—group, or a (C₁₋₈ alkyl)₂amino-S (O)₂— group and the C₁₋₈ alkyl isdescribed above. Specifically, examples thereof include an aminosulfonylgroup, a methylaminosulfonyl group and a dimethylaminosulfonyl group.

The “(C₁₋₈ alkyl)_(x)-aminosulfonyl group which may be substituted”means an unsubstituted aminosulfonyl group or a (C₁₋₈alkyl)_(x)-aminosulfonyl group in which one or two hydrogen atoms on thenitrogen atom or the alkyl moiety are substituted by a definedsubstituent(s). When two substituent groups are present, eachsubstituent group can be the same or different from each other.

The “C₁₋₈ alkoxycarbonyl (C₀₋₈ alkyl) amino group” means a C₁₋₈alkoxy-C(O)—NH— group or a C₁₋₈ alkoxy-C(O)—N(C₁₋₈ alkyl)- group,wherein the C₁₋₈ alkoxy group and C₁₋₈ alkyl) are described above.Specifically, examples thereof include a methoxycarbmamoyl group and anN-ethylcarbonyl-N-methyl-amino group.

The “C₁₋₈ alkoxycarbony(C₀₋₈ alkyl) amino group which may besubstituted” means the unsubstituted C₁₋₈ alkoxycarbony(C₀₋₈ alkyl)amino group described above, or a C₁₋₈ alkoxycarbony(C₀₋₈ alkyl) aminogroup, wherein at least one hydrogen atom of the alkyl moiety issubstituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. Preferably, it is a C₁₋₈ alkoxycarbony(C₀₋₈ alkyl)amino group which may be substituted by 1 to 3 substituent(s).

The “C₁₋₈ alkoxycarbonyl (C₀₋₈ alkyl) aminosulfonyl group” means a C₁₋₈alkoxy-C(O)—NHS(O)₂— group or a C₁₋₈ alkoxy-C(O)—N(C₁₋₈ alkyl)S(O)₂—group, wherein the C₁₋₈ alkoxy group and C₁₋₈ alkyl group are describedabove. Specifically, examples thereof include amethoxycarbonylaminosulfonyl group and anethoxycarbonyl-N-methyl-aminosulfonyl group.

The “C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl) amino group” means a C₆₋₁₀aryl-O—C(O)—NH— group or a C₆₋₁₀ aryl-O—C(O)—N(C₁₋₈ alkyl)- group,wherein the C₆₋₁₀ aryl group and C₁₋₈ alkyl are described above.Specifically, examples thereof include a phenyloxycarbonylamino groupand a N-methyl-N-phenyloxycarbonyl-amino group.

The “C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl) amino group which may besubstituted” means the unsubstituted C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl)amino group described above or the C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl)amino group in which at least one hydrogen atoms of the aryl moiety issubstituted by a defined substituent(s). When two or more substituentgroups are present, each substituent group can be the same or differentfrom each other. Preferably, it is a C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl)amino group which may be substituted by 1 to 3 substituent(s).

The “C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈ alkyl) amino group”means a C₆₋₁₀ aryl NHC(O)NH— group, a C₆₋₁₀ aryl-N(C₁₋₈ alkyl)-C(O)NH—group, a C₆₋₁₀ aryl-N(C₁₋₈ alkyl)-C(O)N(C₁₋₈ alkyl)- group, or a C₆₋₁₀aryl-NH—C(O)N(C₁₋₈ alkyl)- group, wherein the C₆₋₁₀ aryl group and C₁₋₈alkyl are described above. Specifically, examples thereof include aphenylaminocarbonylamino group and a phenylaminocarbonyl(N-methyl)aminogroup.

The “C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈ alkyl) amino groupwhich may be substituted” means the unsubstituted C₆₋₁₀ aryl (C₀₋₈alkyl) aminocarbonyl (C₀₋₈ alkyl) amino group described above or theC₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈ alkyl) amino group in whichat least one hydrogen atoms of the aryl moiety is substituted by adefined substituent(s). When two or more substituent groups are present,each substituent group can be the same or different from each other.Preferably, it is a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈ alkyl)amino group which may be substituted by 1 to 3 substituent(s).

The “C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyloxy group” means a C₆₋₁₀aryl-NHC(O)—O—, or a C₆₋₁₀ aryl-N(C₁₋₈ alkyl)-C(O)—O— group, wherein theC₆₋₁₀ aryl group and C₁₋₈ alkyl are described above. Specifically,examples thereof include a phenylaminocarbonyloxy group and aphenylaminocarbonyl(N-methyl)amino carbonyloxy group.

The “C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyloxy group which may besubstituted” means the unsubstituted C₆₋₁₀ aryl (C₀₋₈ alkyl)aminocarbonyloxy group described above or the C₆₋₁₀ aryl (C₀₋₈ alkyl)aminocarbonyloxy group in which at least one hydrogen atoms of the arylmoiety is substituted by a defined substituent(s). When two or moresubstituent groups are present, each substituent group can be the sameor different from each other. Preferably, it is a C₆₋₁₀ aryl (C₀₋₈alkyl) aminocarbonyloxy group which may be substituted by 1 to 3substituent(s).

The “C₁₋₈ alkylsulfonyl (C₀₋₈ alkyl) amino group” means a C₁₋₈alkyl-S(O)₂—NH— group, or a C₁₋₈ alkyl-S(O)₂—N(C₁₋₈ alkyl)- group.Specifically, examples thereof include a methylsulphonylamino group anda methylsulphonyl-(N-methyl)amino group.

The “C₂₋₈ alkenyloxy group” means a C₂₋₈ alkenyl-O— group, wherein theC₂₋₈ alkenyl group is described above. Specific examples of the C₂₋₈alkenyloxy group include a vinyloxy group and a allyloxy group.

Preferably, all of A¹, A², A³, A⁴, A⁷, A⁸, A⁹ and A¹⁰ are C, or any oneof A², A⁴, A⁷ and A⁹ is N and the remainings are C (with the provisothat, when A², A⁴, A⁷ or A⁹ is N, they do not have a substituent groupR², R⁴, R⁷ or R⁹). More preferably, all of them are C, or A⁴ is N whilethe remainings are C, even more preferably, all of them are C, or A⁴,A⁷, and A⁹ is N and the remainings are C (with the proviso that, whenA⁴, A⁷, or A⁹ is N, they do not have a substituent group R⁴, R⁷, R⁹).

A⁵ is preferably NR⁵ or O, more preferably NR⁵, even more preferably NH.

-   -   R¹ is preferably        [1] a hydrogen atom,        [2] a halogen atom,        and more preferably        [1] a hydrogen atom,        [2] a fluorine atom,        [3] a chlorine atom.    -   R¹⁰ is preferably a hydrogen atom.    -   R² is preferably        [1] a hydrogen atom,        [2] a C₁₋₅ alkyl group,        [3] a cyano,        [4] a halogen atom,        and more preferably        [1] a hydrogen atom,        [2] a C₁₋₃ alkyl group,        [3] a fluorine atom,        [4] a chlorine atom,        [5] a bromine atom.        And even more preferably        [1] a hydrogen atom,        [2] a halogen atom,        Still more preferably        [1] a hydrogen atom,    -   R⁴ is preferably        [1] a hydrogen atom,        [2] a C₁₋₅ alkyl group which may be substituted by 1-11 halogen        atom(s),        [3] a C₃₋₆ cycloalkyl group,        [4] a cyano,        [5] a halogen atom,        [6] a (C₁₋₃ alkyl)_(m4b)-amino group (m4b: 0˜2),        [7] a hydroxy,        [8] a C₁₋₅ alkoxy group which may be substituted by 1-4        hydroxy(s),        and more preferably        [1] a hydrogen atom,        [2] a C₁₋₃ alkyl group which may be substituted by 1-7 halogen        atom(s),        [3] a C₃₋₅ cycloalkyl group,        [4] a cyano,        [5] a florine atom,        [6] a bromine atom,        [7] an amino (C₁₋₃ alkyl)_(m4b)-amino group,        [8] a hydroxy,        [9] a C₁₋₃ alkoxy group which may be substituted by 1-2        hydroxy(s).        Even more preferably        [1] a hydrogen atom,        [2] a C₁₋₈ alkyl group which may be substituted by at least one        halogen atom,        [3] a C₃₋₈ cycloalkyl group,        [4] a cyano,        [5] a halogen atom,        [6] a hydroxy,        [7] a C₁₋₈ alkoxy group which may be substituted by a hydroxy,        Still more preferably        [1] a hydrogen atom,        [1] a halogen atom,    -   R⁵ is preferably        [1] a hydrogen atom,        [2] a C₁₋₅ alkyl group which may be substituted by 1-5 R^(5A)        substituent(s),        [3] a C₁₋₅ alkylsulfonyl group,        and more preferably        [1] a hydrogen atom,        [2] a C₁₋₃ alkyl group which may be substituted by 1-3 R^(5A)        substituent(s),        [3] a C₁₋₃ alkylsulfonyl group.        Even more preferably        [1] a hydrogen atom,        [2] a C₁₋₈ alkyl group,        Still more preferably        [1] a hydrogen atom.    -   R^(5A) is preferably        [1] a C₁₋₅ alkoxycarbonyl group,        [2] a hydroxy,        [3] a C₁₋₅ alkoxy group,        [4] a (C₁₋₅ alkyl)_(m5)-amino group (m5: 0-2),        [5] a C₆ aryl,        [6] a C₁₋₅ alkylthio group,        and more preferably        [1] a C₁₋₃ alkoxycarbonyl group,        [2] a hydroxy,        [3] a C₁₋₃ alkoxy group,        [4] a (C₁₋₃ alkyl)_(m5)-amino group (m5: 0-2),        [5] a C₁₋₃ alkylthio group,        even more preferably        [1] a hydroxy,        [2] a C₁₋₅ alkoxy group,        [3] a (C₁₋₅ alkyl)_(m5)-amino group (m5: 0-2),        [4] a C₁₋₅ alkylthio group.    -   R⁶ and R^(6′) are preferably        [1] a C₁₋₈ alkyl group,        taken together with carbon atoms to which they are bound to form        [2] a C₃₋₈ cycloalkyl group,        [3] a 4- to 10-membered heterocycloalkyl group,        more preferably        [1] a C₁₋₃ alkyl group,        taken together with carbon atoms to which they are bound to form        [2] a C₃₋₆ cycloalkyl group,        [3] a 4- to 6-membered heterocycloalkyl group,        even more preferably        [1] a methyl,        taken together with carbon atoms to which they are bound to form        [2] a cyclopentane,        [3] a tetrahydropyran,        [4] or a piperidine.    -   R⁷ is preferably        [1] a hydrogen atom,        [2] a fluorine atom,        [3] a bromine atom,        [4] a chlorine atom,        [5] a C₁₋₅ alkoxy group which may be substituted by 1-4 R^(7A)        substituent(s),        and more preferably        [1] a hydrogen atom,        [2] a halogen atom,        and even more preferably        [1] a hydrogen atom,        [2] a fluorine atom,        [3] a bromine atom,        [4] a chlorine atom,        and still more preferably        [1] a hydrogen atom.    -   R^(7A) is preferably        [1] a (C₁₋₅ alkyl)_(m7)-amino group (m7: 0˜2),        [2] a hydroxy,        [3] a 4- to 6-membered heterocycloalkyl group which may be        substituted by C₁₋₅ alkyl group(s), and more preferably        [1] a (C₁₋₃ alkyl)_(m7)-amino group (m7: 2),        [2] a hydroxy,        [3] a 4- to 6-membered heterocycloalkyl group which may be        substituted by C₁₋₃ alkyl group(s).    -   R³ is preferably        [1] a hydrogen atom,        [2] a C₁₋₅ alkyl group which may be substituted by 1-11 halogen        atom(s),        [3] a cyano,        [4] a (C₁₋₅ alkyl)_(m3a)-aminocarbonyl group (m3a: 0˜2) which        may be substituted by 1-5 R^(3A) substituents,        [5] a hydroxycarbonyl,        [6] a C₁₋₅ alkylcarbonyl group which may be substituted by 1-4        hydroxy(s),        [7] a halogen atom,        [8] a (C₁₋₃ alkyl)_(m3b)-amino group (m3b: 0˜2) which may be        substituted by 1-2 C₆ aryl(s),        [9] a C₁₋₅ alkyl carbonyl (C₀₋₃ alkyl) amino group which may be        substituted by 1-2 C₆ aryl(s) or 1-2 C₆ aryloxy(s),        [10] a C₆ arylcarbonyl (C₀₋₃ alkyl) amino group which may be        substituted by 1-5 C₁₋₃ alkyl group(s) which may be substituted        by 1-7 halogen atom(s),        [11] a (C₁₋₃ alkyl)_(m3c)-aminocarbonyl(C₀₋₃ alkyl) amino group        (m3c: 0-1) which may be substituted by a C₆ aryl,        [12] a nitro,        [13] a hydroxy,        [14] a C₁₋₅ alkoxy group which may be substituted by 1-4        R^(3B)(s),        [15] a 4- to 6-membered heterocycloalkyloxy group,        [16] a 6-membered heteroaryloxy,        [17] a (C₁₋₅ alkyl)_(m3e)-aminocarbonyloxy group (m3e: 0˜2)        which may be substituted by 1-3 C₆ aryl(s),        [18] a 4- to 6-membered nitrogen-containing        heterocycloalkylaminocarbonyl group,        [19] a C₁₋₅ alkylthio group,        [20] a 5- to 6-membered heteroaryl group which may be        substituted by 1-4 C₁₋₅ alkyl group(s) which may be substituted        by 1-3 C₁₋₅ alkoxy group(s),        [21] a C₁₋₃ alkoxycarbonyl C₀₋₃ alkyl) amino group which may be        substituted by a C₁₋₃ alkoxy group,        [22] a C₆ aryloxycarbonyl C₀₋₃ alkyl) amino group which may be        substituted by 1-3 C₁₋₃ alkyl group(s) which may be substituted        by 1-9 halogen atom(s),        [23] a C₆ aryloxycarbonyl C₀₋₃ alkyl) aminocarbonyl C₀₋₃        alkyl)amino group which may be substituted by 1-3 R^(3C),        [24] a C₃₋₆ cycloalkyl C₀₋₃ alkyl) aminocarbonyloxy group, and        [25] a C₆ aryl C₀₋₃ alkyl) aminocarbonyloxy group which may be        substituted by 1-3 substituent(s) selected from the group        consisting of a C₁₋₅ alkyl group and a C₁₋₅ alkoxy group(s).    -   R³ is more preferably        [1] a hydrogen atom,        [2] a C₁₋₃ alkyl group which may be substituted by 1-7 halogen        atom(s),        [3] a cyano,        [4] a (C₁₋₄ alkyl)_(m3a)-aminocarbonyl group (m3a: 0˜1) which        may be substituted by 1-4 R^(3A) substituents,        [5] a hydroxycarbonyl,        [6] a halogen atom,        [7] a C₁₋₄ alkyl carbonyl (C₁₋₃ alkyl) amino group which may be        substituted by 1-2 C₆ aryl(s) or 1-2 C₆ aryloxy(s),        [8] a C₆ arylcarbonyl C₀₋₃ alkyl) amino group which may be        substituted by a C₁₋₃ alkyl group which may be substituted by        1-7 halogen atom(s),        [9] a nitro,        [10] a hydroxy,        [11] a C₁₋₄ alkoxy group which may be substituted by 1-3 R^(3B)        substituent(s),        [12] a 4-membered heterocycloalkyloxy group,        [13] a (C₁₋₃ alkyl)_(m3e)-aminocarbonyloxy group (m3e: 1) which        may be substituted by a C₆ aryl(s),        [14] a 6-membered nitrogen-containing        heterocycloalkylaminocarbonyl group,        [15] a C₁₋₃ alkylthio group,        [16] a 5-membered heteroaryl group which may be substituted by a        C₁₋₅ alkyl group which may be substituted by a C₁₋₃ alkoxy        group,        [17] a C₆ aryloxycarbonyl C₀₋₃ alkyl) aminocarbonyl C₀₋₃        alkyl)amino group which may be substituted by a R^(3C)        substituent,        [18] a C₆ cycloalkyl (C0-2 alkyl) aminocarbonyloxy group, and        [19] a C₆ aryl C₀₋₃ alkyl) aminocarbonyloxy group which may be        substituted by 1-2 substituent(s) selected from the group        consisting of a C₁₋₄ alkyl group and a C₁₋₃ alkoxy group.    -   R³ is still more preferably        [1] a hydrogen atom,        [2] a cyano,        [3] a halogen atom,        R³ is still even more preferably        [1] a cyano,        [2] a halogen atom.    -   R^(3A) is preferably        [1] a C₆ aryl,        [2] a C₁₋₅ alkoxy group,        [3] a 5- or 6-membered heteroaryl group,        [4] a C₆ arylsulfonyl.    -   R^(3B) is preferably        [1] a hydroxy,        [2] a C₁₋₅ alkoxy group,        [3] a C₆ aryl C₀₋₃ alkyl) aminocarbonyl group,        [4] a (C₁₋₃ alkyl)_(m3d)-amino group (m3d: 0˜2),        [5] a halogen atom,        more preferably        [1] a hydroxy,        [2] a C₁₋₅ alkoxy group.    -   R^(3C) is preferably        [1] a C₁₋₅ alkyl group which may be substituted by 1-11 halogen        atom(s),        [2] a C₁₋₅ alkoxy group,        more preferably        [1] a C₁₋₄ alkyl group which may be substituted by 1-9 halogen        atom(s),        [2] a C₁₋₃ alkoxy group.    -   R⁸ is preferably        [1] a hydrogen atom,        [2] a C₁₋₅ alkyl group which may be substituted by 1-5 R^(8A)        substituent(s),        [3] a C₂₋₅ alkenyl group,        [4] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-4 R^(8B) substituent(s),        [5] a 5- to 6-membered heteroaryl group which may be substituted        by 1-4 C₁₋₈ alkyl group(s),        [6] a (C₁₋₅ alkyl)_(m8g)-aminocarbonyl group (m8g: 0˜2) which        may be substituted by 1-3 R^(8C) substituent(s),        [7] a 4- to 6-membered heterocycloalkyl C₀₋₃ alkyl)        aminocarbonyl group which may be substituted by 1-2 oxo        group(s),        [8] a 4- to 6-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by 1-4        R^(8D) substituent(s),        [9] a hydroxycarbonyl,        [10] a C₁₋₅ alkoxy (C₀₋₃ alkyl) aminocarbonyl group which may be        substituted by 1-3 hydroxy group(s),        [11] a halogen atom,        [12] a (C₁₋₅ alkyl)_(m8j)-amino group (m8j:0˜2) which may be        substituted by 1-2 R^(8H) substituent(s),        [13] a hydroxyl,        [14] a C₁₋₅ alkoxy group which may be substituted by 1-4 R^(8E)        substituent(s),        [15] a 4- to 6-membered heterocycloalkyloxy group which may be        substituted by 1-5 R^(8F) substituent(s),        [16] a 6-membered heteroaryloxy group,        [17] a (C₁₋₅ alkyl)_(m8l1)-aminosulfonyloxy group (m8l1: 0-2),        [18] a C₁₋₅ alkyl thio group which may be substituted by 1-4        R^(8I) substituent(s),        [19] a C₁₋₅ alkylsulfonyl group which may be substituted by 1-4        R^(8G) substituent(s),        [20] a 6-membered heterocycloalkylsulfonyl group which may be        substituted by a C₁₋₃ alkyl group,        [21] a C₂₋₅ alkenyloxy group, and        [22] a C₁₋₃ alkylsulfonyloxy group which may be substituted by        1-7 halogen atom(s).        And more preferably        [1] a hydrogen atom,        [2] a C₁₋₃ alkyl group which may be substituted by 1-3 R^(8A)        substituent(s),        [3] a C₂₋₄ alkenyl group,        [4] a 6-membered heterocycloalkyl group which may be substituted        by 1-3 R^(8B) substituent(s),        [5] a 5- to 6-membered heteroaryl group which may be substituted        by 1-2 C₁₋₃ alkyl group(s),        [6] a (C₁₋₃ alkyl)_(m8g)-aminocarbonyl group (m8g: 0˜2) which        may be substituted by 1-2 R^(8C) substituent(s),        [7] a 4- to 6-membered heterocycloalkyl (C₀₋₁ alkyl)        aminocarbonyl group which may be substituted by 1-2 oxo        group(s),        [8] a 6-membered nitrogen-containing heterocycloalkylcarbonyl        group which may be substituted by 1-2 R^(8D) substituent(s),        [9] a hydroxycarbonyl,        [10] a C₁₋₃ alkoxy (C₀₋₃ alkyl) aminocarbonyl group which may be        substituted by 1-2 hydroxy group(s),        [11] a bromine atom,        [12] a (C₁₋₃ alkyl)_(m8j)-amino group (m8j: 0˜2) which may be        substituted by 1-2 R^(8H) substituent(s),        [13] a hydroxyl,        [14] a C₁₋₅ alkoxy group which may be substituted by 1-3 R^(8E)        substituent(s),        [15] a 4- to 6-membered heterocycloalkyloxy group which may be        substituted by 1-3 R^(8F) substituent(s),        [16] a 6-membered heteroaryloxy group,        [17] a (C₁₋₃ alkyl)_(m8l1)-aminosulfonyloxy group (m8l1: 0-2),        [18] a C₁₋₃ alkyl thio group which may be substituted by 1-2        R^(8I) substituent(s),        [19] a C₁₋₃ alkylsulfonyl group which may be substituted by 1-2        R^(8G) substituent(s),        [20] a 6-membered heterocycloalkylsulfonyl group which may be        substituted by a C₁₋₃ alkyl group,        [21] a C₂₋₃ alkenyloxy group, and        [22] a trifluoromethylsulfonyloxy group,        Even more preferably        [1] a hydrogen atom,        [2] a C₁₋₃ alkyl group which may be substituted by 1-3 R^(8A)        substituent(s),        [3] a 6-membered heterocycloalkyl group which may be substituted        by 1-3 R^(8B) substituent(s),        [4] a 5- to 6-membered heteroaryl group which may be substituted        by 1-2 C₁₋₃ alkyl group(s),        [5] a 4- to 6-membered heterocycloalkyl (C0-1 alkyl)        aminocarbonyl group which may be substituted by 1-2 oxo        group(s),        [6] a 6-membered nitrogen-containing heterocycloalkylcarbonyl        group which may be substituted by 1-2 R^(8D) substituent(s),        [7] a (C₁₋₃ alkyl)_(m8j)-amino group (m8j: 0˜2) which may be        substituted by 1-2 R^(8H) substituent(s),        [8] a hydroxyl,        [9] a C₁₋₅ alkoxy group which may be substituted by 1-3 R^(8E)        substituent(s),        [10] a 4- to 6-membered heterocycloalkyloxy group which may be        substituted by 1-3 R^(8F) substituent(s),        [11] a 6-membered heteroaryloxy group,        [12] a C₁₋₃ alkyl thio group which may be substituted by 1-2        R^(8I) substituent(s),        [13] a C₁₋₃ alkylsulfonyl group which may be substituted by 1-2        R^(8G) substituent(s), and        [14] a C₂₋₃ alkenyloxy group,        further preferably        [1] a hydrogen atom,        [2] a C₁₋₃ alkyl group which may be substituted by 1-3 R^(8A)        substituent(s),        [3] a 6-membered heterocycloalkyl group which may be substituted        by 1-3 R^(8B) substituent(s),        [4] a (C₁₋₃ alkyl)_(m8j)-amino group (m8j: 0˜2) which may be        substituted by 1-2 R^(8H) substituent(s),        [5] a C₁₋₅ alkoxy group which may be substituted by 1-3 R^(8E)        substituent(s), and        [6] a 4- to 6-membered heterocycloalkyloxy group which may be        substituted by 1-3 R^(8F) substituent(s),        Still more preferably        [1] a 4- to 10-membered heterocycloalkyl group which may be        substituted by one or more        R^(8B) described below,        Still even more preferably        [1] a 4- to 10-membered heterocycloalkyl group which may be        substituted by at least one halogen atom, C₁₋₈ alkyl group, or        an oxo.    -   R^(8A) is preferably        [8A-1] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-4 R^(8A1) substituent(s),        [8A-2] a (C₁₋₅ alkyl)_(m8a)-amino group (m8a: 0-2) which may be        substituted by 1-11 halogen atom(s), and        [8A-3] a hydroxy;    -   R^(8A) is more preferably        [8A-1] a 6-membered heterocycloalkyl group which may be        substituted by 1-2 R^(8A1) substituent(s),        [8A-2] a (C₁₋₃ alkyl)_(m8a)-amino group (m8a: 0-2) which may be        substituted by 1-11 halogen atom(s), and        [8A-3] a hydroxy;    -   R^(8A1) is preferably        [8A1-1] a C₁₋₅ alkyl group,        [8A1-2] a C₁₋₅ alkylsulfonyl group,        [8A1-3] a (C₁₋₅ alkyl)_(m8b)-aminosulfonyl group (m8b: 0˜2), or        [8A1-4] an oxo group,        more preferably        [8A1-1] a C₁₋₃ alkyl group,        [8A1-2] a C₁₋₃ alkylsulfonyl group, or        [8A1-3] a (C₁₋₃ alkyl)_(m8b)-aminosulfonyl group (m8b: 0),    -   R^(8B) is preferably        [8B-1] a C₁₋₆ alkyl group which may be substituted by 1-13        R^(8B1) substituent(s),        [8B-2] a C₂₋₆ alkynyl group,        [8B-3] a C₃₋₆ cycloalkyl group which may be substituted by [1]        cyano(s) or [2] C₁₋₆ alkyl group(s),        [8B-4] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-10 R^(8B2) substituent(s),        [8B-5] a C₁₋₆ alkoxy group which may be substituted by 1-5        substituent(s) selected from the group consisting of [1] a C₁₋₅        alkoxy group and [2] a C₃₋₆ cycloalkyl group,        [8B-6] a C₁₋₅ alkoxycarbonyl group,        [8B-7] a C₁₋₅ alkylsulfonyl group,        [8B-8] a 5- to 6-membered heteroarylsulfonyl group,        [8B-9] a cyano,        [8B-10] a C₁₋₆ alkanoyl group which may be substituted by 1-2        R^(8B3) substituent(s),        [8B-11] a C₃₋₈ cycloalkylcarbonyl group,        [8B-12] a (C₁₋₅ alkyl)_(m8c)-aminosulfonyl group (m8c: 0-2),        [8B-13] a C₁₋₆ alkylsulfonyl (C₀₋₆ alkyl) amino group,        [8B-14] a (C₁₋₈ alkyl)_(m8d)-amino group (m8d: 0-2) which may be        substituted by 1-3 R^(8B4) substituent(s),        [8B-15] a hydroxy,        [8B-16] a (C₁₋₆ alkyl)_(m8e)-aminocarbonyl group (m8e: 0-2), or        [8B-17] a C₁₋₄ alkoxycarbonylamino group        more preferably        [8B-1] a C₁₋₅ alkyl group which may be substituted by 1-3        R^(8B1),        [8B-2] a C₂₋₅ alkynyl group,        [8B-3] a C₃₋₅ cycloalkyl group which may be substituted by [1] a        cyano or [2] a C₁₋₆ alkyl group,        [8B-4] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-8 R^(8B2) substituent(s),        [8B-5] a C₁₋₅ alkoxy group which may be substituted by 1-2        substituent(s) selected from the group consisting of [1] a C₁₋₃        alkoxy group and [2] a C₃₋₆ cycloalkyl group,        [8B-6] a C₁₋₃ alkylsulfonyl group,        [8B-7] a cyano,        [8B-8] a C₁₋₆ alkanoyl group which may be substituted by a        R^(8B3) substituent,        [8B-9] a C₃₋₅ cycloalkylcarbonyl group,        [8B-10] a (C₁₋₃ alkyl)_(m8c)-aminosulfonyl group (m8c: 1-2),        [8B-11] a C₁₋₃ alkylsulfonyl (C₀₋₃ alkyl) amino group,        [8B-12] a (C₁₋₅ alkyl)_(m8d)-amino group (m8d: 0-1) which may be        substituted by 1-2 R^(8B4) substituent(s),        [8B-13] a hydroxy, or        [8B-14] a (C₁₋₃ alkyl)_(m8e)-aminocarbonyl group (m8e: 0-1).    -   R^(8B1) is preferably        [8B1-1] a C₃₋₆ cycloalkyl group,        [8B1-2] a hydroxy,        [8B1-3] a C₁₋₈ alkoxy group which may be substituted by 1-2 C₁₋₅        alkoxy group(s), or        [8B1-4] a cyano,        More preferably        [8B1-1] a C₃₋₅ cycloalkyl group,        [8B1-2] a hydroxy,        [8B1-3] a C₁₋₈ alkoxy group which may be substituted by 1 C₁₋₃        alkoxy group, or        [8B1-4] a cyano,    -   R^(8B2) is preferably        [8B2-1] a halogen atom,        [8B2-2] a C₁₋₆ alkyl group,        [8B2-3] an oxo,        [8B2-4] a hydroxy, or        [8B2-5] a deuterium atom, more preferably        [8B2-1] a fluorine atom,        [8B2-2] a C₁₋₃ alkyl group,        [8B2-3] an oxo, or        [8B2-4] a hydroxyl.

R^(8B3) is preferably

[8B3-1] a (C₁₋₆ alkyl)_(m8f)-amino group (m8f: 0-2),more preferably[8B3-1] a (C₁₋₃ alkyl)_(m8f)-amino group (m8f: 2).

-   -   R^(8B4) is preferably        [8B4-1] a C₃₋₆ cycloalkyl group, or        [8B4-2] a hydroxy;    -   R^(8C) is preferably        [8C-1] a hydroxyl,        [8C-2] a (C₁₋₃ alkyl)_(m8h)-amino group (m8h: 0-1) which may be        substituted by a (C₁₋₃ alkyl)_(m8i)-aminosulfonyl group (m8i:        0-2),        [8C-3] a C₁₋₃ alkylsulfonyl group,    -   R^(8D) is preferably        [8D-1] a C₁₋₆ alkyl group which may be substituted by a R^(8D1)        substituent,        [8D-2] a hydroxy group,        [8D-3] a C₁₋₃ alkylsulfonyl group, or        [8D-4] a C₁₋₄ alkoxycarbonyl group;    -   R^(8D1) is preferably        [8D1-1] a hydroxy group, or        [8D1-2] a C₁₋₃ alkoxy group;    -   R^(8H) is preferably        [8H-1] a 4- to 6-membered heterocycloalkyl group,    -   R^(8E) is preferably        [8E-1] a hydroxy group,        [8E-2] a C₁₋₈ alkoxy group which may be substituted by 1-2        R^(8E7) substituent(s),        [8E-3] a C₁₋₃ alkylsulfonyl group,        [8E-4] a C₁₋₄ alkoxycarbonyl group,        [8E-5] a 4- to 6-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by 1-2        R^(8E1) substituent(s),        [8E-6] a (C₁₋₅ alkyl)_(m8k1)-amino group (m8k1: 0˜2) which may        be substituted by a R^(8E2) substituent,        [8E-7] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-4 R^(8E3) substituent(s),        [8E-8] a 5- to 6-membered heteroaryl group,        [8E-9] a (C₁₋₆ alkyl)_(m8k2)-aminocarbonyl group (m8k2: 0˜2)        which may be substituted by 1-2 R^(8E6) substituent(s),        [8E-10] a C₁₋₅ alkoxy group which may be substituted by a        R^(8E7) substituent,        [8E-11] a C₁₋₃ alkylthio group,        [8E-12] a C₁₋₃ alkylsulfinyl group,        [8E-13] a C₁₋₅ alkylsulfonyl group,        [8E-14] a C₁₋₃ alkylsulfonyl (C₀₋₈ alkyl) amino group,        [8E-15] a 4- to 6-membered heterocycloalkylsulfonyl (C₀₋₃ alkyl)        amino group which may be substituted by 1-3 C₁₋₅ alkyl group(s);        more preferably        [8E-1] a (C₁₋₃ alkyl)_(m8k1)-amino group (m8k1: 2) which may be        substituted by one or more R^(8E2),        [8E-2] a C₁₋₈ alkoxy group which may be substituted by one or        more R^(8E7),        [8E-3] a C₁₋₃ alkylsulfonyl group,        [8E-4] a (C₁₋₅ alkyl)_(m8k1)-amino group (m8k1: 0˜2) which may        be substituted by a R^(8E2) substituent,        [8E-5] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-4 R^(8E3) substituent(s),        [8E-6] a 4- to 6-membered heterocycloalkylsulfonylamino group        which may be substituted by 1-2 C₁₋₃ alkyl group(s);    -   R^(8E1) is preferably        [8E1-1] a C₁₋₄ alkoxycarbonyl group,        [8E1-2] a C₁₋₃ alkanoyl group,        [8E1-3] a C₁₋₅ alkylsulfonyl group,        [8E1-4] a (C₁₋₃ alkyl)_(m8k3)-aminosulfonyl group (m8k3: 0˜2),        [8E1-5] a 4- to 6-membered heterocycloalkyl group;    -   R^(8E2) is preferably        [8E2-1] a hydroxy group,        [8E2-2] a C₁₋₆ alkoxycarbonyl group,        [8E2-3] a C₃₋₆ cycloalkyl group which may be substituted by a        C₁₋₈ alkyl group which may be substituted by a hydroxy,        [8E1-4] a C₁₋₅ alkanoyl group which may be substituted by 1-3        substituent(s) selected from the group consisting of [1] a (C₁₋₃        alkyl)_(m8k4)-amino group (m8k4: 0˜2) and [2] a halogen atom,        [8E2-5] a (C₁₋₃ alkyl)_(m8k5)-aminocarbonyl group (m8k5: 0˜2),        [8E2-6] a C₁₋₃ alkylsulfonyl group,        [8E2-7] a (C₁₋₃ alkyl)_(m8k6)-aminosulfonyl group (m8k6: 0-1)        which may be substituted by a C₁₋₄ alkoxycarbonyl group.        more preferably        [8E2-1] a hydroxy group.    -   R^(8E3) is preferably        [8E3-1] a C₁₋₆ alkyl group which may be substituted by 1-3        substituent(s) selected from the group consisting of [1] a        hydroxy group or [2] a C₁₋₃ alkylcarbonyloxy group,        [8E3-2] a C₁₋₄ alkylcarbonyloxy group,        [8E3-3] a hydroxy group,        [8E3-4] a C₃₋₅ cycloalkyl group,        [8E3-5] a C₁₋₄ alkoxycarbonyl group,        [8E3-6] a C₁₋₅ alkylsulfonyl group,        [8E3-7] a (C₁₋₃ alkyl)_(m8k8)-aminocarbonyl group (m8k8: 0˜2),        [8E3-8] a C₁₋₃ alkanoyl group which may be substituted by a        hydroxy,        [8E3-9] an oxo group, or        [8E3-10] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-3 substituent(s) selected from the group        consisting of [1] a C₁₋₃ alkanoyl group, [2] a C₁₋₄        alkoxycarbonyl group, or [3] a C₁₋₃ alkylsulfonyl group;        more preferably        [8E3-1] a (C₁₋₃ alkyl)_(m8k8)-aminocarbonyl group (m8k8: 0˜2),        or        [8E3-2] an oxo group;    -   R^(8E4) is preferably        [8E4-1] a 4- to 6-membered heterocycloalkyl group,        [8E4-2] a C₁₋₃ alkanoyl group,        [8E4-3] a C₁₋₃ alkoxycarbonyl group,        [8E4-4] a C₁₋₃ alkylsulfonyl group,        [8E4-5] a C₁₋₃ alkylaminosulfonyl group;    -   R^(8E6) is preferably        [8E6-1] a C₂₋₃ alkenylcarbonyloxy group,        [8E6-2] a hydroxy group,        [8E6-3] a cyano,        [8E6-4] a (C₁₋₃ alkyl)_(m8k9)-amino group (m8k9: 0˜2) which may        be substituted by 1-2 hydroxy group(s),        [8E6-5] a C₁₋₃ alkoxy group which may be substituted by a        hydroxy,        [8E6-6] a C₁₋₄ alkylcarbonyloxy group,        [8E6-7] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-3 C₁₋₈ alkyl group(s),        [8E6-8] a 5- to 6-membered heteroaryl group;    -   R^(8E7) is preferably        [8E7-1] a hydroxy group,        [8E7-2] a C₁₋₃ alkoxy group which may be substituted by a        hydroxy;

R^(8F) is preferably

[8F-1] a C₁₋₅ alkyl group which may be substituted by 1-3 R^(8F1)substituent(s),[8F-2] a C₃₋₆ cycloalkyl group,[8F-3] a C₁₋₃ alkanoyl group which may be substituted by 1-7 halogenatom(s),[8F-4] a C₁₋₅ alkylcarbonyloxy group,[8F-5] a C₁₋₅ alkoxycarbonyl group,[8F-6] a 4- to 6-membered heterocycloalkyl group which may besubstituted by 1-3 R^(8F2) substituent(s),[8F-7] a C₁₋₅ alkylsulfonyl group, or[8F-8] a hydroxy group;More preferably[8F-1] a C₁₋₃ alkyl group which may be substituted by a R^(8F1)substituent,][8F-2] a C₃₋₅ cycloalkyl group,[8F-3] a 4- to 6-membered heterocycloalkyl group which may besubstituted by a R^(8F2) substituent,[8F-4] a C₁₋₃ alkylsulfonyl group,

-   -   R^(8F1) is preferably        [8F1-1] a hydroxy group,        [8F1-2] a C₁₋₅ alkoxy group, or        [8F1-3] a halogen atom;    -   R^(8F2) is preferably        [8F2-1] a 4- to 6-membered heterocycloalkyl group,        [8F2-2] a C₁₋₅ alkoxycarbonyl group, or        [8F2-3] a C₁₋₃ alkylsulfonyl group,    -   R^(8G) is preferably        [8G-1] a hydroxycarbonyl group,        [8G-2] a hydroxy group, or        [8G-3] a (C₁₋₅ alkyl)_(m8l3)-amino group (m8l3: 0˜2),    -   R⁹ is preferably        [1] a hydrogen atom,        [2] a C₁₋₈ alkyl group which may be substituted by 1-8 R^(9A)        substituent(s),        [3] a C₂₋₆ alkenyl group,        [4] a C₂₋₈ alkynyl group which may be substituted by 1-6 R^(9C)        substituent(s),        [5] a C₃₋₆ cycloalkyl group,        [6] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-5 R^(9D) substituent(s),        [7] a C₆ aryl group which may be substituted by 1-2 R^(9E)        substituent(s),        [8] a 5- to 6-membered heteroaryl group which may be substituted        by 1-3 C₁₋₅ alkyl group(s),        [9] a cyano,        [10] a C₁₋₆ alkanoyl group,        [11] a 4- to 6-membered nitrogen-containing        heterocycloalkylcarbonyl group which may be substituted by a        C₁₋₅ alkyl group,        [12] a halogen atom,        [13] a (C₁₋₄ alkyl)_(m9c)-amino group (m9c: 0˜2) which may be        substituted by a R^(9F) substituent,        [14] a hydroxy,        [15] a C₁₋₆ alkoxy group which may be substituted by 1-5 R^(9G)        substituent(s),        [16] a 4- to 6-membered heterocycloalkyloxy group which may be        substituted by one or two 4- to 6-membered heterocycloalkyl        group(s),        [17] a C₁₋₅ alkylthio group which may be substituted by (C₁₋₃        alkyl)_(m9f)-amino group(s) (m9f: 0˜2),        [18] a C₁₋₅ alkylsulfonyl group which may be substituted by        (C₁₋₃ alkyl)_(m9g)-amino group(s) (m9g: 0˜2),        [19] a (C₁₋₃ alkyl)_(m9h)-aminosulfonyl group (m9h: 0˜2),        [20] a 4- to 6-membered nitrogen-containing        heterocycloalkylsulfonyl group which may be substituted by a        C₁₋₃ alkyl group;        More preferably        [1] a hydrogen atom,        [2] a C₁₋₆ alkyl group which may be substituted by a R^(9A)        substituent,        [3] a C₂₋₅ alkenyl group,        [4] a C₂₋₈ alkynyl group which may be substituted by a R^(9C)        substituent,        [5] a C₃₋₆ cycloalkyl group,        [6] a 4- to 6-membered heterocycloalkyl group which may be        substituted by a R^(9D) substituent,        [7] a 5- to 6-membered heteroaryl group which may be substituted        by a C₁₋₅ alkyl group,        [8] a cyano,        [9] a C₁₋₃ alkanoyl group,        [10] a halogen atom,        [11] a (C₁₋₄ alkyl)_(m9b)-n amino group (m9b: 0),        [12] a hydroxy,        [13] a C₁₋₆ alkoxy group which may be substituted by 1-3 R^(9G)        substituent(s),        [14] a 4- to 6-membered heterocycloalkyloxy group which may be        substituted by a 4- to 6-membered heterocycloalkyl group,        Even more preferably        [1] a hydrogen atom,        [2] a C₁₋₈ alkyl group which may be substituted by one or more        R^(9A) substituent(s),        [3] a C₂₋₈ alkenyl group which may be substituted by one or more        R^(9B) substituent(s),        [4] a C₂₋₈ alkynyl group which may be substituted by one or more        R^(9C) substituent(s),        [5] a C₃₋₈ cycloalkyl group,        [6] a halogen atom,        Still more preferably        [1] a hydrogen atom,        [2] a C₁₋₈ alkyl group which may be substituted by one or more        R^(9A) substituent(s),        [3] a C₂₋₈ alkynyl group which may be substituted by one or more        R^(9C) substituent(s).        R^(9A) is preferably        [9A-1] a C₃₋₆ cycloalkyl group,        [9A-2] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-3 R^(9A1) substituent(s),        [9A-3] a hydroxy group, or        [9A-4] a C₁₋₆ alkoxy group,        More preferably        [9A-1] a 4- to 6-membered heterocycloalkyl group which may be        substituted by a R^(9A1) substituent,        [9A-2] a hydroxy group, or        [9A-3] a C₁₋₃ alkoxy group,    -   R^(9A1) is preferably        [9A1-1] a C₁₋₅ alkyl group,        [9A1-2] a C₃₋₅ cycloalkyl group, or        [9A1-3] a 4- to 6-membered heterocycloalkyl group,        More preferably        [9A1-1] a C₁₋₃ alkyl group,        [9A1-2] a C₃ cycloalkyl group, or        [9A1-3] a 4-membered heterocycloalkyl group,    -   R^(9C) is preferably        [9C-1] a C₁₋₈ alkoxy group,        [9C-2] a (C₁₋₅ alkyl)_(m9b)-amino group (m9b: 0˜2) which may be        substituted by 1-2 C₆ aryl group(s),        [9C-3] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-3 R^(9C1) substituent(s),        [9C-4] a C₃₋₆ cycloalkyl group,        [9C-5] a hydroxy group, or        [9C-6] a hydroxycarbonyl group;        More preferably        [9C-1] a C₁₋₅ alkoxy group,        [9C-2] a (C₁₋₃ alkyl)_(m9b)-amino group (m9b: 2) which may be        substituted by 1-2 C₆ aryl group(s),        [9C-3] a 4- to 6-membered heterocycloalkyl group which may be        substituted by 1-2 R^(9C1) substituent(s),        [9C-4] a C₃₋₅ cycloalkyl group,        [9C-5] a hydroxy group.    -   R^(9C1) is preferably        [9C1-1] a C₃₋₅ cycloalkyl group,        [9C1-2] a 4- to 6-membered heterocycloalkyl group, or        [9C1-3] an oxo group,        More preferably        [9C1-1] a C₃ cycloalkyl group,        [9C1-2] a 4- to 6-membered heterocycloalkyl group, or        [9C1-3] an oxo group,    -   R^(9D) is preferably        [9D-1] a C₁₋₅ alkyl group which may be substituted by one or two        4- to 6-membered heterocycloalkyl group(s),        [9D-2] a C₃₋₅ cycloalkyl group,        [9D-3] a 4- to 6-membered heterocycloalkyl group, or        [9D-4] a C₁₋₃ alkylsulfonyl group;        More preferably        [9D-1] a C₁₋₅ alkyl group which may be substituted by a 4- to        6-membered heterocycloalkyl group,        [9D-2] a 4- to 6-membered heterocycloalkyl group, or        [9D-3] a methylsulfonyl group;    -   R^(9E) is preferably        [9E-1] a halogen atom,        [9E-2] a hydroxy group,        [9E-3] a hydroxycarbonyl group, or        [9E-4] a C₁₋₃ alkyl group which may be substituted by a hydroxy;    -   R^(9F) is preferably        [9F-1] a C₁₋₃ alkylsulfonyl group,        [9F-2] a (C₁₋₃ alkyl)_(m9f1)-aminosulfonyl group (m9f1: 0˜2), or        [9F-3] a C₁₋₃ alkanoyl group which may be substituted by (C₁₋₃        alkyl)_(m9f2)-amino group(s) (m9f2: 0˜2),    -   R^(9G) is preferably        [9G-1] a hydroxy group,        [9G-2] a hydroxycarbonyl group,        [9G-3] a C₆ aryl group which may be substituted by C₁₋₃ alkoxy        group(s),        [9G-4] a (C₁₋₃ alkyl)_(m9g1)-amino group (m9g1: 0˜2),        [9G-5] a C₁₋₅ alkoxy group which may be substituted by 1-3        R^(9G1) substituent(s), or        [9G-6] a 5- to 6-membered heteroaryl group;        More preferably        [9G-1] a hydroxy group,        [9G-2] a (C₁₋₃ alkyl)_(m9g1)-amino group (m9g1: 0˜2),        [9G-3] a C₁₋₃ alkoxy group which may be substituted by a R^(9G1)        substituent, or        [9G-4] a 5- to 6-membered heteroaryl group;    -   R^(9G1) is preferably        [9G1-1] a C₁₋₃ alkoxy group, or        [9G1-2] a hydroxycarbonyl group.

Preferably, A⁵ is NH, while the remaining are C, R³ is a cyano group, R⁶and R^(6′) are methyl, R⁸ is (1) a hydrogen atom, (2) a C₁₋₈ alkyl groupwhich may be substituted by one or more R^(8A), (3) a C₂₋₈ alkenylgroup, (4) a 4- to 10-membered heterocycloalkyl group which may besubstituted by one or more R^(8B), (5) a 5- to 14-membered heteroarylgroup which may be substituted by a C₁₋₈ alkyl group, (6) a (C₁₋₈alkyl)_(m8g)-aminocarbonyl group which may be substituted by one or moreR^(8C), (7) a 4- to 10-membered nitrogen-containingheterocycloalkylcarbonyl group which may be substituted by one or moreR^(8D), (8) a hydroxycarbonyl group, (9) a C₀₋₈ alkoxy (C₀₋₈ alkyl)aminocarbonyl group which may be substituted by one or more hydroxygroup(s), (10) a halogen atom, (11) a hydroxy group, (12) a C₁₋₈ alkoxygroup which may be substituted by one or more R^(8E), (13) a 4- to10-membered heterocycloalkyloxy group which may be substituted by one ormore R^(8F), (14) an aminosulfonyloxy group which may be substituted byone or more C₁₋₈ alkyl group(s), (15) a C₁₋₈ alkyl thio group which maybe substituted by a (C₁₋₈ alkyl)_(n)-amino group, or (16) a C₁₋₈alkylsulfonyl group which may be substituted by R^(8G), R⁹ is (1) ahydrogen atom, (2) a C₁₋₈ alkyl group which may be substituted by one ormore R^(9A), (3) a C₂₋₈ alkenyl group which may be substituted by one ormore R^(9B), (4) a C₂₋₈ alkynyl group which may be substituted by one ormore R^(9C), (5) a C₃₋₈ cycloalkyl group, (6) a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(9D),(7) a C₆₋₁₀ aryl group which may be substituted by one or more R^(9E),(8) a 5- to 14-membered heteroaryl group which may be substituted by aC₁₋₈ alkyl group, (9) a cyano group, (10) a C₁₋₈ alkanoyl group, (11) a4- to 10-membered nitrogen-containing heterocycloalkylcarbonyl groupwhich may be substituted by a C₁₋₈ alkyl group, (12) a halogen atom,(13) a (C₁₋₈ alkyl)_(m9c)-amino group which may be substituted by one ormore R^(9F), (14) a C₁₋₈ alkylsulfonylamino group, (15) a nitro group,(16) a hydroxy group, (17) a C₁₋₈ alkoxy group which may be substitutedby one or more R^(9G), (18) a C₁₋₈ alkyl thio group which may besubstituted by a (C₁₋₈ alkyl)_(m9f)-amino group, (19) a C₁₋₈alkylsulfonyl group which may be substituted by a (C₁₋₈alkyl)_(m9g)-amino group, (20) a (C₁₋₈ alkyl)_(m9h)-aminosulfonyl group,or (21) a 4- to 10-membered nitrogen-containing heterocycloalkylsulfonylgroup which may be substituted by a C₁₋₈ alkyl group, and R¹, R², R⁵, R⁷and R¹⁰ are defined above.

More preferably, A⁵ is NH while the remaining are C, R³ is a cyanogroup, R⁶ and R^(6′) are methyl groups, R⁸ is (1) a hydrogen atom, (2) aC₁₋₈ alkyl group which may be substituted by one or more R^(8A), (3) a4- to 10-membered heterocycloalkyl group which may be substituted by oneor more R^(8B), or (4) a C₁₋₈ alkoxy group which may be substituted byone or more R^(8E), R⁹ is (1) a hydrogen atom, (2) a C₁₋₈ alkyl groupwhich may be substituted by one or more R^(9A), (3) a C₂₋₈ alkynyl groupwhich may be substituted by one or more R^(9C), (4) a C₃₋₈ cycloalkylgroup, or (5) a halogen atom, and R¹, R², R⁵, R⁷ and R¹⁰ are an hydrogenatom.

According to the present invention, examples of the salts of thecompounds that are represented by the Formula (I) include hydrochloricacid salt, hydrobromic acid salt, hydriodic acid salt, phosphoric acidsalt, phosphonic acid salt, sulfuric acid salt, sulfonic acid salt suchas methanesulfonic acid salt, p-toluene sulfonic acid salt and the like,carboxylic acid salt such as acetic acid salt, citric acid salt, malicacid salt, tartaric acid salt, succinic acid salt, salicylic acid saltand the like, or alkali metal salt such as sodium salt, potassium saltand the like, alkaline earth metal salt such as magnesium salt, calciumsalt and the like, ammonium salt such as ammonium salt, alkyl ammoniumsalt, dialkyl ammonium salt and trialkyl ammonium salt tetraalkylammonium salt. Preferably, the salts are pharmaceutically acceptablesalts. These salts are produced by brining the compounds described abovein contact with an acid or a base which can be used for the productionof a pharmaceutical product.

According to the present invention, the compounds that are representedby the Formula (I) or salts thereof can be an anhydride or a solvatesuch as a hydrate and the like. Herein, the term “solvate (d)” indicatesa phenomenon by which solute molecules or ions contained in a solutionstrongly attract neighboring solvent molecules to form a huge group ofmolecules. When the solvent is water, it is called “hydrate (d).” Thesolvate can be any one of a hydrate and a non-hydrate. Preferably, thesolvates are pharmaceutically acceptable solvates. For the non-hydrate,alcohol (for example, methanol, ethanol, n-propanol), dimethylformamideand the like can be used.

The compounds of the present invention and salts thereof may be presentin several tautomer forms, for example, enol and imine form, keto andenamine form, and a mixture thereof. In a solution, a tautomer ispresent as a mixture of tautomeric set. In case of solid form, one typeof tautomer is generally present in dominant ratio. In this regard, evenif only one type of tautomer is described, the present inventionincludes all types of tautomer of the compounds of the presentinvention.

The present invention includes all types of stereoisomer of thecompounds of the present invention that are represented by the Formula(I) (for example, enantiomer, diastereomer (including cis and transgeometric isomer)), racemate of the isomer and a mixture thereof. Forexample, the compounds having the Formula (I) of the present inventionmay have one or more asymmetric center, and the present inventionincludes a racemic mixture, a diastereomer mixture and enantiomer ofsuch compound.

When the compounds of the present invention are obtained in free form,they can be converted into a salt, a hydrate or solvate thereof whichcan be formed from the compounds according to a method generally knownin the art.

Further, when the compounds of the present invention are obtained in theform of a salt, hydrate or solvate of the compounds, they can beconverted to free form according to a method generally known in the art.

The present invention include all isotopes of compounds that arerepresented by the Formula (I). The isotopes of the compounds of thepresent invention indicate the compounds of the present invention inwhich at least one atom is substituted by an atom with the same atomicnumber (i.e., number of protons) but with different mass number (sum ofthe number of protons and the number of neutrons). Example of theisotopes that are included in the compounds of the present inventionincludes a hydrogen atom, a carbon atom, a nitrogen atom, an oxygenatom, a phosphorus atom, a sulfur atom, a fluorine atom, a chlorine atomand the like, and ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F,³⁶Cl and the like are included. In particular, a radioisotope whichdecays by emitting radiation, for example ³H and ¹⁴C, are useful fordetermining the distribution of a pharmaceutical agent or a compound ina living tissue, etc. On the other hand, a stable isotope does notdegrade and remains in almost the same amount without exhibitingradioactivity, and therefore can be safely used. Isotopes of thecompounds of the present invention can be converted by replacing achemical reagent used for synthesis with a chemical reagent comprising acorresponding radioisotope according to a method generally known in theart.

Further, the compounds (I) of the present invention can be administeredin the form of prodrug. Herein, the term “prodrug” indicates thederivatives of the compounds having the Formula (I) that can beconverted to the compounds having the Formula (I) or salts or solvatesthereof after administration by enzymatic or non-enzymatic degradationunder a physiological condition. The prodrug can be in inactive formwhen it is administered to a patient. However, in organisms, it convertsto the compounds having the Formula (I) and present therein in theactive form.

For example, the prodrug converts into desired drug form at specific pHor by an enzymatic action. Conventional prodrug is a compound having ahydrolyzable ester residue which produces a free acid in organisms.Examples of such hydrolyzable ester residue include a residue having acarboxyl moiety of which free hydrogen (for example, a free hydrogen ina carboxyl group when Y in the Formula (I) has a carboxyl group) isreplaced by a C₁₋₄ alkyl group, a C₂₋₇ alkanoyloxymethyl group, a1-(alkanoyloxy)ethyl group having 4 to 9 carbon atoms, a1-methyl-1-(alkanoyloxy)-ethyl group having 5 to 10 carbon atoms, analkoxycarbonyloxymethyl group having 3 to 5 carbon atoms, a1-(alkoxycarbonyloxy)ethyl group having 4 to 7 carbon atoms, a1-methyl-1-(alkoxycarbonyloxy)ethyl group having 5 to 8 carbon atoms, aN-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, a1-(N-(alkoxycarbonyl)amino)ethyl group having 4 to 10 carbon atoms, a3-phthalidyl group, a 4-crotonolactonyl group, a γ-butyrolacton-4-ylgroup, a di-N,N—(C₁₋₂)alkylamino(C₂₋₃)alkyl group (for example,N,N-dimethylaminoethyl group), a carbamoyl(C₁₋₂)alkyl group, aN,N-di(C₁₋₂)alkylcarbamoyl-(C₁₋₂)alkyl group, a piperidino(C₂₋₃)alkylgroup, a pyrrolidino(C₂₋₃)alkyl group, or a morpholino(C₂₋₃) alkylgroup, but not limited thereto.

Representative Preparation Method

The compounds having the Formula (I) of the present invention can beproduced by the method described below, for example. However, method ofpreparing the compounds of the present invention is not limited thereto.Further, depending on necessity, order of the reaction step likeintroduction of a substituent group, etc. can be changed. Although thecompounds of the present invention are novel compounds which have notbeen described in literatures, they can be prepared according to achemical method that is generally known in the art. Still further, asfor the reacting compounds that are used for the preparation,commercially available ones can be used or they can be producedaccording to a method that is generally known in the art depending onnecessity.

In the following reaction schemes showing the reaction step, A¹ to A¹⁰and R¹ to R¹⁰ are as defined in the Formula (I). PR¹ to PR¹⁰ are thesame as R¹ to R¹⁰ that are defined in the Formula (I) or represent agroup which can be converted to R¹ to R¹⁰ according to modification ordeprotection of a functional group.

Other abbreviated symbols described in the following reaction schemeshave the general meanings that can be understood by a skilled person inthe art.

PG represents a protecting group (for example, methyl, ethyl, t-butyl,benzyl, substituted benzyl, acetyl, t-butoxycarbonyl, benzyloxycarbonyl,methanesulfonyl, trifluoromethanesulfonyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,tetrahydropyranyl and the like). In the preparation method describedbelow, when a defined group is subjected to undesirable chemicalmodification under a condition for implementing the method, thepreparation can be carried out by using means such as protection anddeprotection of a functional group, etc.

Herein, regarding selection, addition and removal of a protecting groupinclude the methods described in “Protective Groups in OrganicSynthesis” (Greene and Wuts, 4^(th) edition, John Wiley & Sons 2007),and they can be suitably employed according to each reaction condition.

LG represents a leaving group such as fluorine, chlorine, bromine,iodine, methanesulfonate, trifluoromethanesulfonate and the like, whichcan be applied for the reaction described above.

In addition, abbreviated symbols that are typically used to describe thegeneral synthetic method and examples below and names of the chemicalreagents and solvents corresponding to the chemical formulae are listedin the following.

-   -   9-BBN 9-borabicyclo[3.3.1]nonane    -   AcOH acetic acid    -   BINAP 2,2′-bis (diphenylphosphino)-1,1′-binaphthyl    -   BF₃OEt₂ trifluoroboron etherate    -   t-BuOK potassium t-butoxy    -   n-BuLi n-butyl lithium    -   t-BuONa sodium t-butoxy    -   CDI carbonyl diimidazole    -   CPME c-pentylmethyl ether    -   DBU 1,8-diazabicyclo[5.4.0]-7-undecene    -   DCM dichloromethane    -   DEAD diethyl azodicarboxylate    -   DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone    -   DIPEA N,N-diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DME dimethoxyethane    -   DMF N,N-dimethyl formamide    -   DMSO dimethyl sulfoxide    -   DPPF bis (diphenylphosphino)ferrocene    -   EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride    -   EtOAc ethyl acetate    -   HOBt 1-hydroxybenzotriazole    -   KHMDS potassium hexamethyldisilazide    -   LDA lithium diisopropylamide    -   LiHMDS lithium hexamethyldisilazide    -   MeCN acetonitrile    -   MeI methyl iodide    -   MeOH methanol    -   MTBE t-butylmethyl ether    -   NaHMDS sodium hexamethyldisilazide    -   NMP N-methylpyrrolidone    -   Pd₂(dba)₃ tris (dibenzylideneacetone) dipalladium (0)    -   Pd(OAc)₂ palladium acetate    -   PdCl₂(CH₃CN)₂ dichloro(bisacetonitrile) palladium (II)    -   PdCl₂(PPh₃)₂ dichlorobis (triphenylphosphine) palladium (II)    -   Pd(PPh₃)₄ tetrakis (triphenylphosphine) palladium (0)    -   P(t-Bu)₃ tri t-butylphosphine    -   PPh₃ triphenylphosphine    -   P(o-tol)₃ tri o-tolylphosphine    -   TEA triethylamine    -   TEMPO 2,2,6,6-tetramethylpiperidin-1-oxyl    -   TFA trifluoroacetic acid    -   TFAA trifluoroacetic anhydride    -   TFE trifluoroethanol    -   THF tetrahydrofuran    -   TMAD 1,1′-azobis (N,N-dimethylformamide)    -   TMSCl trimethylsilyl chloride    -   TMSI trimethylsilyl iodide    -   DavePhos 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl    -   JohnPhos 2-(di-t-butylphosphino)biphenyl    -   c-Hexyl JohnPhos 2-(dicyclohexylphosphino)biphenyl    -   S-Phos 2′,6′-dimethoxy-2-(dicyclohexylphosphino)biphenyl    -   X-Phos 2′,4′,6′-triisopropyl-2-(dicyclohexylphosphino)biphenyl    -   t-ButylX-Phos        2′,4′,6′-triisopropyl-2-(di-t-butylphosphino)biphenyl    -   Xantphos 4,5′-bis (diphenylphosphino)-9,9′-dimethylxanthene

Preparation Method I

This is one of the methods for producing the compounds of the Formula(I) in which A⁵ is N and R⁵ is H.

Step I-1

It is an alkylation step of a cyclic ketone derivative Ia. The step canbe carried out by reacting cyclic ketone derivative Ia with analkylating agent corresponding to R⁶ and R^(6′) in the presence of abase. For example, it can be carried out in view of the method describedin Journal of the American Chemical Society, 115(23), 10628-36; 1993 andOrganic Letters, 9(24), 5027-5029; 2007, etc. The reaction is carriedout in a solvent under the condition of a reaction temperature of −20°C. to boiling point of the solvent, in the presence or the absence of acatalyst. When R⁶ and R^(6′) are atomic groups other than a hydrogenatom, the reaction order can be optionally selected, and separation andpurification can be carried out at each step or the reaction can becarried out continuously.

As for the alkylating agent, examples thereof include an alkyl halidesuch as MeI, ethyl iodide, 2-iodopropane, 1,4-dibromobutane, 1,1′-oxybis(2-bromoethane) and the like, dimethyl sulfate, and sulfonic acid estersuch as methylmethanesulfonate, methyl tosylate andmethyltrifluoromethanesulfonate. Preferably, it is an alkyl halide suchas MeI and the like. As for the catalyst, examples thereof include aphase transfer catalyst such as tetrabutylammonium chloride andtetrabutylammonium hydrogen sulfate. Preferably, it istetrabutylammonium hydrogen sulfate. As for the base, examples thereofinclude an inorganic base such as sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride,potassium hydride, calcium hydride and the like or an organic base suchas t-BuOK, t-BuONa, pyridine, TEA, DIPEA, LDA, LiHMDS and n-BuLi.Preferably, it is potassium hydroxide, potassium t-butoxy, or sodiumt-butoxy. As for the solvent, examples thereof include toluene, xylene,n-hexane, cyclohexane, DMF, DMA, EtOAc, DMSO, dichloromethane, carbontetrachloride, THF, dioxane, acetonitrile, water, methanol, ethanol anda mixture thereof. Preferably, it is a mixture solvent of water-THF orTHF.

Step I-2

It is the synthesis of carbazole skeleton Id according to Fischermethod. This step is generally carried out by using cyclic ketone Ib inthe presence of hydrazine compound Ic and an acid in a solvent or byusing an acid as a solvent under the condition of a reaction temperatureof 0° C. to boiling point of the solvent, and also can be carried out inview of the method described in Journal of Heterocyclic Chemistry,28(2), 321-3; 1991 and Bioorganic & Medicinal Chemistry Letters (2008),18(24), 6479-6481. Further, when the reaction proceeds slowly, a zincchloride catalyst and the like can be also used in view of the reactioncondition disclosed in Organic Letters (2006), 8(3), 367-370. Thereaction consists of a step of producing phenyl hydrazone and a step ofsigmatropic rearrangement. Separation and purification can be carriedout at each step or the reaction can be carried out continuously.Further, according to the structure of aryl hydrazine, which is areacting material of this reaction step, mixture of a position isomercan be obtained as a reaction product. Such position isomer can beseparated from each other or used as a mixture for the next reactionstep.

As for the acid used for the reaction, examples thereof include formicacid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid,benzenesulfonic acid, TFA, hydrochloric acid, sulfuric acid andpyridinium p-toluenesulfonate. Preferably, it is acetic acid, sulfuricacid, or TFA. As for the solvent, examples thereof include toluene,xylene, NMP, DMF, DMA, DMSO, sulfolane, dioxane, DME, TFE, diethyleneglycol, triethylene glycol and a mixture thereof.

Step I-3

It is a step of oxidation at benzyl at 11-position of carbazole skeletonId. This step is carried out by applying an oxidizing agent to asubstrate in a solvent in the presence or absence of a catalyst underthe condition of a reaction temperature of −20° C. to boiling point ofthe solvent. As for the reaction condition, the method described inJournal of Medicinal Chemistry, 51(13), 3814-3824; 2008, etc. can beconsidered.

As for the oxidizing agent and the catalyst used for the reaction, DDQ,peracid such as, mCPBA and the like, cerium ammonium nitrate (IV) (CAN),permanganate such as potassium permanganate, barium permanganate and thelike, sodium chlorite, hydrogen peroxide, or N-hydroxyphthalimide andthe like can be used alone or in a combination thereof. Preferably, itis DDQ or N-hydroxyphthalimide. As for the reaction solvent used for thereaction, examples thereof include water, t-butanol, acetonitrile, THF,dichloromethane, ethyl acetate and a mixture thereof. Preferably, it isTHF.

Preparation Method II

It is an exemplary method of producing 3-ketoester intermediate IIg,which is used for constructing the skeleton of the compounds that arerepresented by the Formula (I).

Step II-1, Step II-2

It is an alkylation step at α position of carboxylic acid ester IIc ornitrile IIa. The step can be carried out by reacting with an alkylatingagent corresponding to R⁶ and R^(6′) in a solvent under the condition ofa reaction temperature of −20° C. to boiling point of the solvent, inthe presence of a base. For example, it can be carried out in view ofthe method described in J. Org. Chem., 2007, 72 (25), 9541-9549 andEuropean Journal of Organic Chemistry (21), 3449-3462, etc. The reagentsand the condition for the reaction are the same as those described forStep I-1.

Step II-3

It is an ester hydrolysis step of carboxylic acid ester IId. This stepcan be carried out by hydrolysis in an aqueous solvent at the reactiontemperature of 0° C. to boiling point of the solvent in the presence ofan inorganic base, for example in view of the method described inTetrahedron Lett. 3529, 1977. Alternatively, it can be carried outaccording to a method in which hydrolysis is carried out in the presenceof an acid, in view of the method described in J. Am. Chem. Soc, 1977,99, 2353, for example. As for the inorganic base, examples thereofinclude sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate and cesium carbonate. Preferably, it is sodiumhydroxide or potassium hydroxide. As for the solvent, water, methanol,ethanol, tetrahydrofuran, dioxane, and the like can be used alone or ina combination thereof. Preferably, it is methanol comprising water orethanol comprising water. As for the acid which can be used for acidhydrolysis, hydrochloric acid, sulfuric acid, trifluoroacetic acid andmethanesulfonic acid can be used alone in a combination thereof.Preferably, it is sulfuric acid.

Step II-4, Step II-5

It is a direct (hetero)arylation step at α position of carboxylic acidester or nitrile. This step can be carried out by S_(N)Ar reaction inwhich carboxylic acid ester or nitrile is reacted with aromatic compoundIIf having a leaving group in the presence of a base. It can be carriedout in view of the method described in J. Am. Chem. Soc. 2000, 122,712-713. Alternatively, it can be also carried out according to a methodin which carboxylic acid ester or nitrile is reacted with aromaticcompound IIf having a leaving group in the presence of a catalyst, aligand and a base. For example, it can be carried out in view of themethod described in Org. Lett, 2008, 10(8), 1545, J. Org. Chem. 2003,68, 8003 and Angew. Chem. Int. Ed. 2003, 42, 5051, etc.

As for the base used for the reaction, sodium phosphate, potassiumphosphate, sodium carbonate, potassium carbonate, cesium carbonate,sodium hydride, LiHMDS, NaHMDS, LDA, lithium dicyclohexylamide, lithium2,2,6,6-tetramethyl pyrrolidide, KHMDS, t-BuONa, t-BuOK and the like canbe used. Preferably, it is NaHMDS, KHMDS, or t-BuONa. As for thecatalyst, ligand, or catalyst-ligand complex which are used for thereaction, palladium acetate, Pd₂(dba)₃, π-allyl palladium chloridedimer, PdCl₂(CH₃CN)₂, trialkylproazaphosphatrane, {P(t-Bu)₃PdBr}₂, PPh₃,P(o-tol)₃, BINAP, DPPF, P(t-Bu)₃, DavePhos, JohnPhos, c-Hexyl JohnPhos,S-Phos, X-Phos, t-ButylX-Phos, Xantphos, 4,5-bis[bis(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene,1,3-diallyldihydroimidazolium salt and the like can be used, forexample. Preferably, it is triisobutylproazaphosphatrane.

Step II-6

It is a step of hydrolyzing nitrile IIb to carboxylic acid. This stepcan be carried out by hydrolysis in the presence of an acid under thecondition of a reaction temperature of 0° C. to boiling point of thesolvent, and the reaction conditions include that described in, forexample, Tetrahedron, 64(36), 8464-8475; 2008, etc. For the reaction,the acid itself can be used as a solvent or diluted with other solvent.Alternatively, it can be carried out by hydrolysis in the presence of aninorganic base under the condition of a reaction temperature of 0° C. toboiling point of the solvent, and the reaction condition described in,for example, Bioorganic & Medicinal Chemistry Letters, 18(2), 749-754;2008, etc. can be employed.

The reaction consists of the hydrolysis of nitrile IIb to acid amide andfurther conversion into carboxylic acid. Separation and purification canbe carried out at each step or the reaction can be carried outcontinuously.

As for the acid which is used for the reaction, examples thereof includemethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,trifluoroacetic acid, hydrochloric acid and sulfuric acid. As for thesolvent, examples thereof include toluene, xylene, dioxane,dimethoxyethane, diethylene glycol, triethylene glycol, TFE and the likeand a mixture thereof. As for the inorganic base, examples thereofinclude sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate and cesium carbonate.

Step II-7

It is a step of converting carboxylic acid IIe to β-ketoester. Accordingto this step, the carboxylic acid as a reacting material is convertedinto an acid chloride, active ester and the like by an action of anactivating agent in a solvent under the condition of a reactiontemperature of 0° C. to boiling point of the solvent. Thereafter, theacid chloride or active ester is reacted with enolate of malonic acidmonoester under the condition of a reaction temperature of 0° C. toboiling point of the solvent to give a target compound throughdecarboxylation. As for the reaction condition, a method described in J.Chem. Soc. Perkin Trans. 1 1988, 2345-2352 and Synthesis 1993, 290-292can be used, for example. As for the method of activating carboxylicacid, examples thereof include a method of converting into an acidchloride by using thionyl chloride, oxalyl chloride, phosphorusoxychloride, etc. or a method of converting into an active ester byusing CDI. Preferably, thionyl chloride or CDI is used. The activatedcarboxylic acid itself can be subjected to separation and purification,or can be used continuously for the next reaction. As for the method ofproducing an enolate of malonic acid monoester, a combination ofmagnesium salt like magnesium chloride, etc. and malonic acid monoester(and a salt thereof) or a Grignard reagent like i-propyl magnesiumchloride, etc. and malonic acid monoester (and a salt thereof), etc. canbe used. In order to improve the reaction yield, an organic base such asTEA, DIPEA and the like can be also added to the reaction system. As forthe solvent, examples thereof include toluene, xylene, MeCN, THF, CPME,MTBE, NMP, DMF, DMA, DMSO, sulfolane, dioxane, DME, and the like and amixture thereof. Preferably, it is MeCN, THF or DME.

Step II-8

It is a step of converting nitrile IIb to 3-ketoester. This step can becarried out by so-called Blaise reaction in which 2-halo carboxylic acidester is reacted with nitrile in the presence of activated zinc powderunder the condition of a reaction temperature of 0° C. to boiling pointof the solvent, and the reaction method described in, for example,SYNTHESIS 2004, No. 16, pp 2629-2632x. can be used. As for the method ofactivating zinc powder, a method in which acid washing and drying arecarried out in advance, or a method in which a catalytic amount of anacid such as methanesulfonic acid, etc. is included in the reactionsystem can be employed.

Preparation Method III

It is an exemplary method of preparing compound IIIh from intermediateIIg that is obtained from Preparation method II.

Step III-1

This step can be carried out by nucleophilic aromatic substitutionreaction in which an aromatic nitro compound having a leaving group isreacted with β-ketoester IIg in the presence of a base under thecondition of a reaction temperature of 0° C. to boiling point of thesolvent, and the reaction method include that described in, for example,Synlett, (5), 883-885; 2004 and Tetrahedron, 38(23), 3479-83; 1982.

As for the base used for the reaction, sodium phosphate, potassiumphosphate, sodium carbonate, potassium carbonate, cesium carbonate,sodium hydride, LiHMDS, NaHMDS, LDA, lithium dicyclohexylamide, lithium2,2,6,6-tetramethylpyrrolidide, KHMDS, t-BuOK, t-BuONa and the like canbe used. Preferably, it is potassium carbonate, cesium carbonate,t-BuOK, or t-BuONa. As for the solvent, examples thereof includetoluene, xylene, MeCN, THF, CPME, MTBE, NMP, DMF, DMA, DMSO, sulfolane,dioxane, DME, acetone, methylethyl ketone, and a mixture thereof.Preferably, it is THF, DMF, DMA, NMP or a mixture thereof.

Further, the present step can be also carried out in the presence of acatalyst and a base, as described in Step III-5 or Journal of OrganicChemistry, 72(14), 5337-5341; 2007.

Step III-2

It is a reductive cyclization step to form an indole ring following thereduction of a nitro group. This reaction can be carried out by reactingβ-ketoester IIIa with a reducing agent under the condition of a reactiontemperature of 0° C. to boiling point of the solvent to reduce the nitrogroup. As for the reducing agent used for the reaction, the conditiongenerally used for reduction of a nitro group, for example, iron asexemplified in Synthesis, (18), 2943-2952, 2008, zinc as exemplified inTetrahedron, 64(40), 9607-9618, 2008, titanium (III) chloride asexemplified in Organic & Biomolecular Chemistry, 3(2), 213-215, 2005,tin (II) chloride as exemplified in Journal of Organic Chemistry,58(19), 5209-5220, 1993, sodium hydrosulphite as exemplified in GazzettaChimica Italiana, 121(11), 499-504, 1991, and catalytic reductioncondition as exemplified in Synlett, (17), 2689-2691, 2008, etc. can beemployed. Preferably, the reducing agent is iron or sodiumhydrosulphite.

Step III-3

It is a step of deprotecting an ester protecting group ofindole-3-carboxylic acid ester IIIb. As an example of an esterprotecting group, a methyl group, an ethyl group, a t-butyl group, abenzyl group, a substituted benzyl group and the like can be used.Preferably, it is a t-butyl. As for the deprotection, examples thereofinclude a method described in “Protective Groups in Organic Synthesis”(Greene and Wuts, 4^(th) edition, John Wiley & Sons 2007), and it can beappropriately used according to each reaction condition. When the esterprotecting group is a t-butyl, as a deprotection condition, TMSI, TMSCl,and BF₃.OEt₂ can be used. As for the solvent, examples thereof includetoluene, xylene, diethyl ether, THF, CPME, MTBE, NMP, DMF, DMA, DMSO,sulfolane, dioxane, DME, TFE and the like and a mixture thereof.Preferably, it is THF or TFE.

Step III-4

It is a step of cyclizing indole-3-carboxylic acid IIIc to carbazolebased on Friedel-Crafts reaction. According to the reaction, a mixedacid anhydride is formed by using acetic anhydride, trifluoroaceticanhydride and the like, or acid chloride is formed by using thionylchloride, oxalyl chloride, phosphorus oxychloride and the like, whichresults in activiation of the carboxylic acid. Preferably, aceticanhydride or trifluoroacetic anhydride is used. The reaction is carriedout in the absence or presence of a solvent. As for the solvent,examples thereof include toluene, xylene, diethyl ether, THF, CPME,MTBE, NMP, DMF, DMA, DMSO, sulfolane, dioxane, DME and the like and amixture thereof. Preferably, it is THF, DMF, DMA or DME. Further, anorganic base such as TEA, DIPEA, pyridine and the like can be used.

Thereafter, under the condition of a reaction temperature of 0° C. toboiling point of the solvent, the cyclization is carried out without acatalyst or with Bronsted acid or Lewis acid catalyst (Heterocycles1999, 51, 2127). As for the Lewis acid catalyst, examples thereofinclude aluminum chloride, aluminum triflate, bismuth triflate,ytterbium triflate and BF₃.OEt₂. Preferably, it is BF₃.OEt₂. Dependingon the type of a substituent group, it is also possible to carry out thereaction by applying methanesulfonic acid-phosphorus pentoxide (Eatonreagent), polyphosphoric acid and the like to indole-3-carboxylic acidester IIIb without undergoing Step III-3.

Step III-5, III-6

The step can be carried out by reacting an aromatic acylamide compoundhaving a leaving group with β-ketoester IIg in the presence of a base, acatalyst, and a ligand under the condition of a reaction temperature of0° C. to boiling point of the solvent, followed by deprotection of anacyl protecting group. Examples thereof include a method described inJournal of Organic Chemistry 2007, 72, 9329-9334 and Organic Letters10(4), 625-628, 2008. As for the metal catalyst, copper (I) iodide andpalladium acetate can be used. As for the ligand, (S)-proline, trit-butylphosphine, bis (t-butyl) (2′-methyl[1,1′-biphenyl]-2-yl)phosphineand the like can be used. As for the base which is used for thereaction, sodium phosphate, potassium phosphate, sodium carbonate,potassium carbonate, cesium carbonate, sodium hydride, LiHMDS, NaHMDS,LDA, lithium dicyclohexylamide, lithium 2,2,6,6-tetramethylpyrrolidide,potassium hexamethyldisilazide, t-BuONa, t-BuOK and the like can beused.

Step III-7, III-8

It is a step of reacting an aromatic amino compound with β-ketoester IIgto form an enamine intermediate followed by catalytic cyclization.Examples thereof include a method described in Journal of OrganicChemistry, 68(15), 6011-6019; 2003 and European Journal of OrganicChemistry, (24), 3977-3980; 2007.

Alternatively, the cyclization can be carried out based on an oxidativemethod. For example, a reaction condition described in AngewandteChemie, International Edition, 47(38), 7230-7233; 2008 can be alsoemployed, for example.

Step III-9

It is a step of synthesizing 1,3-diketone based on cyclization of β-ketoester IIg. As for the condition and reagents for the reaction, a methoddescribed in Bioorganic & Medicinal Chemistry Letters, 18(2), 568-570;2008 wherein β-keto ester IIg is reacted in an solvent in the presenceof Bronsted acid catalyst or Lewis acid catalyst, or a method of using acondensing agent such as methanesulfonic acid-phosphorus pentoxide(Eaton reagent), polyphosphoric acid and the like can be employed.

Step III-10, III-11

This step can be carried out in the same manner as Step III-1 and III-2or Step III-5 and III-6.

Preparation Method IV

An exemplary method of producing compound IIIh wherein formula Iva isemployed as a starting material.

Step IV-1, IV-3

It is a step of constructing di-substituted indole derivatives based onSonogashira reaction in which a terminal alkyne is reacted with aromaticamine derivative IVa having a leaving group at ortho position in thepresence of a base and a catalyst with or without a catalytic amount ofa copper reagent. Specifically, examples thereof include a methoddescribed in Organic Letters, 11(1), 221-224; 2009. The reaction iscarried out in an appropriate solvent in the presence of a palladiumcatalyst and a ligand (or a complex thereof) with or without a base anda copper catalyst. Example of the copper catalyst used for the reactioninclude copper iodide. As an example of the catalyst and the ligand (ora complex thereof), palladium acetate, Pd₂(dba)₃, π-allyl palladiumchloride dimer, PdCl₂(CH₃CN)₂, PdCl₂(PPh₃)₂, trialkylproazaphosphatrane,{P(t-Bu)₃PdBr}₂, PPh₃, P(o-tol)₃, BINAP, DPPF, P(t-Bu)₃, DavePhos,JohnPhos, c-Hexyl JohnPhos, S-Phos, X-Phos, t-ButylX-Phos, Xantphos,4,5-bis[bis(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene,1,3-diallyldihydroimidazolium salt and the like can be used. As for thebase used for the reaction, sodium phosphate, potassium phosphate,sodium carbonate, potassium carbonate, cesium carbonate, TEA, DIPEA andthe like can be used. Preferably, it is cesium carbonate, TEA or DIPEA.

Step IV-2

This step corresponds to a tandem Friedel-Crafts reaction in whichacylation at 3-position of di-substituted indole derivative IVb iscarried out in the presence of Lewis acid catalyst under the conditionof a reaction temperature of 0° C. to boiling point of the solvent,followed by intramolecular cyclization. As for the catalyst used for thereaction, examples thereof include aluminum chloride, aluminum triflate,bismuth triflate, ytterbium triflate and BF₃.OEt₂. Preferably, it isaluminum chloride.

Step IV-4

This step consists of deprotection of carboxylic acid ester comprised indi-substituted indole derivative IVc and subsequent intramolecularcyclization at 3-position of the indole either in catalytic ornon-catalytic manner. As for the deprotection, examples thereof includea method described in “Protective Groups in Organic Synthesis” (Greeneand Wuts, 4^(th) edition, John Wiley & Sons 2007), and it can beappropriately used according to the type of each protecting group. Whenan activated indole derivative is used for the reaction, cyclizationoccurs more easily so that the reaction can be carried out in anon-catalytic manner. Further, the cylclization can be also carried outby using a condensing agent such as polyphosphoric acid, methanesulfonicacid-phosphorus pentoxide (Eaton reagent) and the like. Alternatively,it is also possible that carboxylic acid is first converted intocarboxylic acid chloride, a mixed acid anhydride and the like under thesame condition as defined in Step III-4 and the cyclization is carriedout under Friedel-Crafts condition in the presence of Lewis acidcatalyst. As for the Lewis acid catalyst used for the reaction, examplesthereof include aluminum chloride, aluminum triflate, bismuth triflate,ytterbium triflate and BF₃.OEt₂.

Preparation Method V

It is one of the methods for constructing the skeleton of the compoundshaving the Formula (I) in which A⁵ is O, S or NH.

Step V-1

It is a step of arylation of cyclic ketone derivative Ib using aromaticcompound Va having a leaving group. The reaction is catalyticallycarried out in the presence of a base with combination of a transitionmetal catalyst and a ligand, and the condition described in J. Am. Chem.Soc. 2000, 122, 1360-1370 and Journal of Organic Chemistry (2003),68(25), 9865-9866 can be used, for example. As for the base used for thereaction, examples thereof include t-BuONa, t-BuOK, LiHMDS, NaHMDS,potassium phosphate, sodium carbonate, potassium carbonate and cesiumcarbonate. As for the catalyst and a ligand (or a catalyst-ligandcomplex), palladium acetate, Pd₂(dba)₃, t-allylpalladium chloride dimer,PdCl₂(CH₃CN)₂, PdCl₂(PPh₃)₂, trialkylproazaphosphatrane,{P(t-Bu)₃PdBr}₂, PPh₃, P(o-tol)₃, BINAP, DPPF, P(t-Bu)₃, DavePhos,JohnPhos, c-Hexyl JohnPhos, S-Phos, X-Phos, t-ButylX-Phos, Xantphos,4,5-bis[bis(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene1,3-diallyldihydroimidazolium salt and the like can be used.

Step V-2

It is a step of deprotecting a protecting group. When A⁵ is O or S, at-butyl group, a benzyl group and a substituted benzyl group can be usedas a protecting group. When A⁵ is O, a t-butyldimethylsilyl group and atetrahydropyranyl group can be used. When it is NH, a t-butoxycarbonylgroup, a benzyloxycarbonyl group, a methanesulfonyl group, atrifluoroacetyl group and the like can be used. As for the deprotection,examples thereof include a method described in “Protective Groups inOrganic Synthesis” (Greene and Wuts, 4^(th) edition, John Wiley & Sons2007), and it can be appropriately used according to the type of eachprotecting group.

Step V-3

It is a cyclization step of cyclic α-aryl ketone derivative Vc to abenzofuran derivative, benzothiophene or indole Vd. The reaction can becarried out under condition of using an acid catalyst or dehydratingcondition. For example, the reaction condition described in ActaPharmaceutica Hungarica (2003), 73(3), 171-178 can be employed. Inaddition, depending on the type of a protecting group for hydroxylgroup, it can be carried out simultaneously with the deprotection ofStep V-2, as described in Heterocycles, 26(7), 1863-71; 1987. Withrespect to the condition for dehydration, a combination of an organicbase and an acid anhydride such as trifluoromethanesulfonic acid and thelike can be used.

Step V-4

It is a step of oxidation at benzyl at 11-position of tetracycliccompound Vd. This step is carried out by applying an oxidizing agent toa substrate in a solvent in the presence or absence of a catalyst underthe condition of a reaction temperature of −20° C. to boiling point ofthe solvent. As for the reaction condition, the method described inJournal of Medicinal Chemistry, 51(13), 3814-3824; 2008, etc. can beemployed.

As for the oxidizing agent and the catalyst used for the reaction, DDQ,peracid such as, mCPBA and the like, cerium ammonium nitrate (IV) (CAN),permanganate such as potassium permanganate, barium permanganate and thelike, sodium chlorite, hydrogen peroxide, N-hydroxyphthalimide and thelike can be used alone or in a combination thereof. As for the solventused for the reaction, examples thereof include water, t-butanol,acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate and amixture thereof.

Preparation Method VI

It is an exemplary method of constructing the skeleton of the compoundsthat are represented by the Formula (I) in which A⁵ is S.

Step VI-1

It is a reaction to construct a benzothiophene ring based on thereaction between ylide VIa having a thiol at ortho position and acylchloride VIb. The reaction can be carried out in the presence of a base,and the condition include that described in Synthesis, (2), 155-7; 1988,for example. As for the base, examples thereof include n-butyl lithium,sodium methylate and triethylamine.

Step VI-2

It is a reaction for the synthesis of an aromatic carboxylic acid. Thereaction can be carried out by metallization like addition of lithium ormagnesium based on exchange between halogen and metal in the presence ofa base, followed by carboxylation using carbonate gas, dry ice, etc. Thereaction condition as described in Journal of Organic Chemistry (2008),73(19), 7785-7788 can be employed. As for the base, n-butyl lithium,s-butyl lithium, t-butyl lithium, a Grignard reagent, and various atecomplexes can be used. Alternatively, as described in e-EROSEncyclopedia of Reagents for Organic Synthesis 2001 (electronic edition;http://www3.interscience.wiley.com/cgi-bin/mrwhome/104554785/HOME),carboxylation condition using a transition metal catalyst can be alsoemployed.

Step VI-3

This step corresponds to intramolecular cyclization at 3-position ofdi-substituted benzothiophene derivative VId either in catalytic ornon-catalytic manner. For example, the reaction condition as describedin Journal of the American Chemical Society, 130(23), 7286-7299; 2008can be employed. The reaction can be carried out by using a condensingagent such as polyphosphoric acid, methanesulfonic acid-phosphoruspentoxide (Eaton reagent) and the like. Alternatively, it is alsopossible that carboxylic acid is first converted into carboxylic acidchloride, a mixed acid anhydride and the like and the cyclization iscarried out under Friedel-Crafts condition in the presence of Lewis acidcatalyst. As for the Lewis acid catalyst used for the reaction, examplesthereof include aluminum chloride, aluminum triflate, bismuth triflate,ytterbium triflate and BF₃.OEt₂.

Preparation Method VII Conversion and Modification of Functional Groups

To the functional groups PR¹ to PR¹⁰ in the Formula (I) of the presentinvention, various substituent groups can be introduced based on amethod of converting and modifying a functional group that is well knownto a skilled person in the pertinent art. Hereinbelow, representativeexamples of functional group conversion will be explained. Further,although the following reaction scheme is specific in that examples ofPR⁸ and PR⁹ are given for the tetracyclic compound that is alreadyconstructed, it can be also carried out to an intermediate during anysteps explained in Preparation methods I to VI above or to a finalcompound. Further, it can be carried out at any substitution position ofPR¹ to PR⁴ and R⁶ to PR¹⁰.

In the following formula, Q¹ and Q² represent any substituent groupwhich constitutes PR¹ to PR⁴ and R⁶ to PR¹⁰.

Step VII-1

It is a step of deprotecting a protecting group for an aromatic hydroxylgroup. As an example of the protecting group, a methyl group, a t-butylgroup, a benzyl group, a substituted benzyl group, at-butyldimethylsilyl group, a tetrahydropyranyl group and the like canbe used. Preferably, it is a methyl group. As for the deprotection,examples thereof include a method described in “Protective Groups inOrganic Synthesis” (Greene and Wuts, 4^(th) edition, John Wiley & Sons2007), and it can be appropriately used according to the type of eachprotecting group. When a methyl group is used as a protecting group,various reaction conditions can be used selectively for the deprotectiondepending on reactivity. Examples thereof include heating in thepresence of pyridine hydrochloric acid salt, heating in the presence ofa solvent with dodecane thiol and sodium methylate and heating in thepresence of a solvent with anhydrous lithium halide, boron tribromide,TMSI and the like.

Step VII-2

It is one of the methods for introducing a substituent group based onformation of ether bond with an aromatic hydroxyl group. For theformation of an ether bond, Mitsunobu reaction described in a knownliterature (Mitsunobu, et. al., Synthesis, Vol. 1, page 1, 1981) or asimilar method can be used. Specifically, the reaction is carried out inthe presence of a phosphorus compound and an azo compound in a solventunder the condition of a reaction temperature of −78° C. to boilingpoint of the solvent. As for the phosphorus compound, examples thereofinclude PPh₃ and tri-n-butylphosphine. As for the azo compound, examplesthereof include DEAD, TMAD and diisopropyl azodicarboxylic acid. Also,by using them in any combination, the target compound can be obtained.

Step VII-3

It is a step of carrying out trifluoromethane sulfonylation on anaromatic hydroxyl group. The reaction is carried out by reacting with areacting reagent such as trifluoromethanesulfonic acid and the like inthe presence of a base with or without a solvent under the condition ofa reaction temperature of −20° C. to boiling point of the solvent. Asfor the base used for the reaction, TEA, DIPEA, pyridine, 2,6-lutidine,dimethylaminopyridine and the like can be used. Preferably, pyridine isused without any solvent. The obtained trifluoromethanesulfonic acidester VIId is a good leaving group and can be used for variousderivatization.

Step VII-4

It is a step of obtaining sulfamic acid ester by carrying outsulfamoylation on an aromatic hydroxyl group. The reaction is carriedout by reacting with a reacting reagent such as sulfamoyl chloride andthe like in the presence of a base with a solvent under the condition ofa reaction temperature of −20° C. to boiling point of the solvent. Asfor the base used for the reaction, sodium hydride, TEA, DIPEA,pyridine, 2,6-lutidine, dimethylaminopyridine and the like can be used.Preferably, it is sodium hydride. The obtained sulfamic acid ester Vileis a substrate for the thiaFries rearrangement of Step VII-5 and can beused for various derivatization.

Step VII-5

This step corresponds to rearrangement of a sulfamoyl group to aneighboring position in the presence of a Lewis acid catalyst under thecondition of a reaction temperature of 0° C. to boiling point of thesolvent when the neighboring position of the sulfamic acid ester isunsubstituted (i.e., C—H), i.e., a reaction called thiaFriesrearrangement. As for the catalyst used for the reaction, aluminumchloride, aluminum triflate, bismuth triflate, ytterbium triflate,BF₃.OEt₂ and the like can be used. Preferably, it is aluminum chloride.

Step VII-6

It is another step of introducing a substituent group based on formationof an ether bond. According to the present step, a reagent having anappropriate leaving group such as alkyl halide and the like is subjectedto nucleophilic reaction with the hydroxyl group of compound VIIb in thepresence of an appropriate base to form an ether bond. As for the base,examples thereof include an inorganic base such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydride, potassiumhydride, calcium hydride and the like or an organic base such aspyridine, TEA, DIPEA and the like.

Further, by using aryl halide, aryl borate and the like as a reagenthaving a leaving group, formation of an diaryl ether bond can be alsoachieved and used. When reactivity is not satisfactory, a catalyst suchas copper powder, copper acetate, copper iodide and the like or a ligandsuch as phenanthroline, trans-1,2-cyclohexanediamine and the like can beused.

Step VII-7

It is a reaction for forming a bond between aryl and a hetero atom byusing compound VIIg having a leaving group. The reaction is carried outin an appropriate solvent inert to the reaction, in the presence of abase. As for the leaving group LG a halogen, triflate and the like canbe used. As for the solvent, examples thereof include toluene, xylene,n-hexane, cyclohexane, DMF, DMA, EtOAc, DMSO, NMP, THF, DME, dioxane,acetonitrile and the like and a mixture thereof. As for the base to beused for the reaction, examples thereof include t-BuONa, t-BuOK, LiHMDS,NaHMDS, KHMDS, potassium phosphate, sodium carbonate, potassiumcarbonate and cesium carbonate. This step can be also carried out byusing a catalyst and a ligand. As for the catalyst and a ligand (or acatalyst-ligand complex), palladium acetate, Pd₂(dba)₃, t-allylpalladiumchloride dimer, PdCl₂(CH₃CN)₂, PdCl₂(PPh₃)₂, trialkylproazaphosphatrane,{P(t-Bu)₃PdBr}₂, PPh₃, P(o-tol)₃, BINAP, DPPF, P(t-Bu)₃, DavePhos,JohnPhos, c-Hexyl JohnPhos, S-Phos, X-Phos, t-ButylX-Phos, Xantphos,4,5-bis[bis(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene,1,3-diallyldihydroimidazolium salt and the like can be used, forexample.

Step VII-8

When the reaction product of Step VII-7 is thio ether VIIh, it ispossible to obtain sulfoxide or sulfone compound VIIj by oxidation withm-chloro perbenzoic acid, oxone, TEMPO and the like.

Step VII-9

It is a reaction for forming a bond between aryl and SP² carbon or abond between aryl and SP³ carbon in which compound VIIg having a leavinggroup is used. The reaction is carried out in an appropriate solventinert to the reaction, in the presence of a base. As for the leavinggroup LG, a halogen, triflate and the like can be used. As for thesolvent, examples thereof include toluene, xylene, n-hexane,cyclohexane, DMF, DMA, EtOAc, DMSO, NMP, THF, DME, dioxane,acetonitrile, water, isopropanol and the like and a mixture thereof. Asfor the base to be used for the reaction, examples thereof includet-BuONa, t-BuOK, LiHMDS, NaHMDS, KHMDS, potassium phosphate, sodiumcarbonate, potassium carbonate, cesium carbonate, TEA and DIPEA. Thisstep can be also carried out by using a catalyst and a ligand. As forthe catalyst and a ligand (or a catalyst-ligand complex), palladiumacetate, Pd₂(dba)₃, t-allylpalladium chloride dimer, PdCl₂(CH₃CN)₂,PdCl₂(PPh₃)₂, trialkylproazaphosphatrane, {P(t-Bu)₃PdBr}₂, PPh₃,P(o-tol)₃, BINAP, DPPF, P(t-Bu)₃, DavePhos, JohnPhos, c-Hexyl JohnPhos,S-Phos, X-Phos, t-ButylX-Phos, Xantphos, 4,5-bis[bis(3,5-bistrifluoromethylphenyl)phosphanyl]-9,9-dimethyl-9H-xanthene,1,3-diallyldihydroimidazolium salt and the like can be used, forexample.

Step VII-10

It is a carboxylation reaction using compound VIIg having a leavinggroup. The reaction is carried out by reacting with formic acid (or asynthetic equivalent thereof) in an appropriate solvent inert to thereaction, in the presence of a base and a catalyst. As for the leavinggroup LG, a halogen, triflate and the like can be used. The solvent andthe catalyst can be selected and used in the same manner as Step VII-9.

Step VII-11

It is an amidation reaction using carboxylic acid VIIm. Specifically,the reaction can be carried out by dehydrating condensation reactionusing various amines such as ammonia, primary amines, secondary amines,hydrazines, substituted hydrazines and the like. The reaction is carriedout in the presence of an acid halogenating agent or a dehydratingcondensing agent in an aprotic solvent under the condition of a reactiontemperature of −20° C. to boiling point of the solvent, with or withoutan active esterifying agent and a base.

As for the acid halogenating agent, examples thereof include oxalylchloride and thionyl chloride. As for the dehydrating condensing agent,examples thereof include 1,3-dicyclohexylcarbodiimide (DCC),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP), EDC and(benzotriazolyloxy)tripyrrolidino-phosphonium=hexafluorophosphate(PyBOP). As for the active esterifying agent, examples thereof includeHOBt, di(N-succinimidyl) carbonate and carbonyl diimidazole. As for thebase, examples thereof include TEA, DIPEA and DBU. As for the solvent,examples thereof include DMF, DMA, DCM, acetone, THF, dioxane, DME,ethyl acetate, MeCN, and a mixture thereof.

Step VII-12

It is a step of forming a bond between aryl and SP carbon using compoundVIIo having a leaving group. The reaction is carried out by reactingterminal alkyne in an appropriate solvent in the presence of a base anda catalyst with or without a catalytic amount of a copper reagent, andthe reaction is referred to as Sonogashira reaction. The reagents andthe condition for the reaction are as defined in Step IV-1 and StepIV-3. As a variant of Sonogashira reaction, examples thereof include amethod disclosed in Tetrahedron, 63(43), 10671-10683; 2007.Specifically, by having secondary amines and the like in a reactionsystem and using propargyl bromide as an alkyne, a propargyl amine canbe introduced.

Step VII-13

It is a reaction of forming a bond between aryl and CN by using compoundVIIo having a leaving group. The reaction can be carried out by addingCN⁻ source in an appropriate solvent in the presence of a copper, zincor palladium catalyst, with or without a ligand, in view of the reactioncondition shown in Organic Letters, 10(23), 5325-5328; 2008, TetrahedronLetters, 49(32), 4693-4694; 2008 and Bioorganic & Medicinal Chemistry,16(13), 6489-6500; 2008. As for the CN⁻ source, copper (I) cyanide, zinc(II) cyanide, iron (III) hexacyanide, sodium cyanide, potassium cyanideand the like can be used.

Synthesis of Starting Materials

Some of the starting materials for the present invention are novelcompounds, and they can be easily synthesized in the same manner asknown reacting compounds or according to the method well known to askilled person in the art.

Hereinabove, examples of a method of preparing the compounds having theFormula (I) according to the present invention are described. However,separation and purification of the target compounds that are describedin detail in each reaction step can be performed by applying commonchemical treatments such as extraction, concentration, removal bydistillation, crystallization, filtration, recrystallization, variouschromatography, etc.

Pharmaceutical of the Present Invention

The pharmaceutical composition of the present invention comprises apharmaceutically acceptable carrier, in addition to the compound that isselected as being useful for the invention. In the presentspecification, the term “pharmaceutically acceptable carrier” means oneor more type of appropriate solid or liquid vehicle, diluent or anencapsulating material which is suitable for administration to mammals.In the present specification, the term “acceptable” means that it doesnot cause any reaction to substantially reduce the pharmaceuticalefficacy of a composition under normal condition for use, and thecomponents of the composition and the subject compound can be mixed wellwith each other. The pharmaceutically acceptable carrier should havesubstantially high purity and substantially low toxicity so that it canbe suitably administered to a subject to be treated, preferably ananimal, and more preferably a mammal.

As the materials which can be used as a pharmaceutically acceptablecarrier, examples thereof include sugars such as lactose, glucose,sucrose, and the like; starch such as corn starch, potato starch and thelike; cellulose and cellulose derivatives such as sodium carboxy methylcellulose, ethyl cellulose, methyl cellulose and the like; tragacanthrubber powder; malt; gelatin; talc; solid lubricating agent such asstearic acid or magnesium stearate and the like; calcium sulfate;vegetable oils such as peanut oil, cotton seed oil, sesame oil, oliveoil, corn oil, plant oil, cacao oil, and the like; polyhydric alcoholssuch as propylene glycol, glycerin, sorbitol, mannitol, polyethyleneglycol and the like; alginic acid; an emulsifying agent such as TWEEN;humectant such as lecithin and the like; colorant; flavor; tablettingagent; stabilizer, anti-oxidant; preservative; pyrogen-free water;aqueous isotonic solution and phosphate buffer solution.

When the pharmaceutical composition of the present invention is used asan ALK inhibitor or a therapeutic or prophylactic agent for aproliferative disorder, or used against depression or cognitive functiondisorder, as an administration route, oral, rectal, parenteral(intravenous, intramuscular, subcutaneous), intracisternal,intravaginal, intraperitoneal, intrabladder, topical (drop, powder,ointment, gel or cream) administration or administration via inhalation(mouth or nasal spray) and the like can be considered. As for theadministration form, examples thereof include a tablet, a capsule, agranule, powder, a pill, an aqueous or non-aqueous oral solution andsuspension, and a parenteral solution which is filled in a containersuitable to be divided into several small dosages. In addition, theadministration form can be modified for various administration routesincluding subcutaneous transplant which gives controlled release of adrug compound.

The aforementioned preparation is prepared according to a methodgenerally known in the art by using additives such as a vehicle, alubricating agent (i.e., coating agent), a binding agent, adisintegrating agent, a stabilizing agent, a corrigent for taste andsmell, a diluent and the like.

As a vehicle, examples thereof include starch such as starch, potatostarch, corn starch, lactose, crystalline cellulose and calcium hydrogenphosphate.

As a coating agent, examples thereof include ethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc,carnauba wax and paraffin.

As a binding agent, examples thereof include polyvinyl pyrrolidone,Macrogol and the compounds described above as a vehicle.

As a disintegrating agent, examples thereof include the compoundsdescribed as a vehicle in the above and a chemically modified starch orcellulose such as sodium croscarmellose, sodium carboxymethyl starch andcrosslinked polyvinyl pyrrolidone.

As a stabilizing agent, examples thereof include paraoxy benzoic acidesters such as methyl paraben, propyl paraben and the like; alcoholssuch as chlorobutanol, benzyl alcohol, phenylethyl alcohol and the like;benzalkonium chloride; phenols such as phenol, cresol and the like;thimerosal; dehydroacetic acid; and sorbic acid.

As a corrigent for taste and smell, examples thereof include asweetener, an acid tasting agent, a flavor and the like that arecommonly used in the art.

Further, as a solvent to prepare a liquid preparation, examples thereofinclude ethanol, phenol, chlorocresol, purified water and distilledwater.

As a surface active agent or an emulsifying agent, examples thereofinclude polysorbate 80, polyoxyl 40 stearate and lauromacrogol.

When the pharmaceutical composition of the present invention is used asan ALK inhibitor or a therapeutic or prophylactic agent for aproliferative disorder, or used against depression or cognitive functiondisorder, the use amount of the compounds of the present invention orsalts or solvates thereof varies depending on symptom, age, body weight,relative health state of a subject, administration of other drugcompounds, administration method and the like. For example, the amountwhich is generally effective for a patient (i.e., warm-blooded animal,in particular human) is, in an effective component (i.e., the compoundof the present invention that is represented by the Formula (I)),preferably 0.001 to 1000 mg per 1 kg body weight per day, morepreferably 0.01 to 300 mg per 1 kg body weight per day in case of anorally administered agent, and dosage per day is preferably in the rangeof 1 to 800 mg for an adult patient with normal body weight. In case ofa parenterally administered agent, it is preferably 0.001 to 1000 mg per1 kg body weight per day, and more preferably, 0.01 to 300 mg per 1 kgbody weight per day. It is preferable to administer them once a day orin divided dosages a day, depending on symptom of a subject to betreated.

EXAMPLE

Hereinbelow, the present invention will be explained in greater detailin view of the following examples. However, the present invention is notlimited by the examples.

NMR Analysis

NMR analysis was carried out by using JNM-EX270 (270 MHz, manufacturedby JEOL), JNM-GSX400 (400 MHz, manufactured by JEOL), or 400 MR (400MHz, manufactured by Varian). NMR data was expressed in ppm (parts permillion; 6), while it was compared with the deuterium lock signalobtained from a sample solvent.

Mass Spectrum

The measurement was carried out by using JMS-DX303 or JMS-SX/SX102A(both manufactured by JEOL).

High Performance Liquid Chromatography—Mass Spectrum Data (LC-MS)

Measurement was carried out by using Micromass (ZMD, manufactured byMicromass) equipped with 996-600E gradient high performance liquidchromatography (manufactured by Waters) or Micromass (ZQ, manufacturedby Micromass) equipped with 2525 gradient high performance liquidchromatography (manufactured by Waters).

One of the following conditions that are described in the Table 1 belowwas taken as a condition for high performance liquid chromatography.

TABLE 1 Analysis Flow Rate Detection Condition Apparatus Column usedColumn Temperature Mobile phase, Gradient (mL/min) Wavelength A ZMDCadenza CD-C18 35 deg. A) 0.05% TFA, H2O B) 0.05% 1.5 210-400 nm(Intakt) 3.0 mm I.D. × TFA, MeCN PDA total 30 mm, 3 um (A/B): 95/5 =>0/100(3.5 min) => 0/100(1 min) B ZMD Cadenza CD-C18 35 deg. A) 0.05%TFA, H2O B) 0.05% 1.0 210-400 nm (Intakt) 3.0 mm I.D. × TFA, MeCN PDAtotal 30 mm, 3 um (A/B): 95/5 => 0/100(9.5 min) => 0/100(2.5 min) C ZQChromolith Flash RP- Room Temp. A) 10 mM AcONH4, H2O B) MeOH 2.0 210-400nm 18e (Merck KGaA) (A/B): 95/5 => 0/100(3 min) => PDA total 4.6 mm I.D.× 25 mm 0/100(2 min) D ZQ Chromolith Flash RP- Room Temp. A) 10 mMAcONH4, H2O B) MeCN 2.0 210-400 nm 18e (Merck KGaA) (A/B): 95/5 =>0/100(3 min) => PDA total 4.6 mm I.D. × 25 mm 0/100(2 min) F ZQ CadenzaCD-C18 35 deg. A) 0.05% TFA, H2O B) 0.05% 1.5 210-400 nm (Intakt) 3.0 mmI.D. × TFA, MeCN PDA total 30 mm, 3 um (A/B): 95/5 => 0/100(3.5 min) =>0/100(1 min) H ZQ Cadenza CD-C18 35 deg. A) 0.05% TFA, H2O B) 0.05% 1.0210-400 nm (Intakt) 3.0 mm I.D. × TFA, MeCN PDA total 30 mm, 3 um (A/B):95/5 => 0/100(9.5 min) => 0/100(2.5 min) I ZQ Ascentis Express C18 RoomTemp. A) 10 mM AcONH4, H2O B) MeOH 1.0 210-400 nm (Sigma Aldrich) (A/B):95/5 => 0/100(9.5 min) => PDA total 2.1 mm I.D. × 50 mm 0/100(1 min) SZQ Sunfire C18 (Waters) Room Temp. A) 0.05% TFA, H2O B) 0.05% 4.0200-400 nm 4.5 mm I.D. × 50 mm, 5 um TFA, MeCN PDA total (A/B): 90/10 =>5/95(3.5 min) => 90/10(1 min) => 90/10(0.5 min) T ZQ Sunfire C18(Waters) Room Temp. A) 0.05% TFA, H2O B) 0.05% 4.0 200-400 nm 4.5 mmI.D. × 50 mm, 5 um TFA, MeCN PDA total (A/B): 90/10 => 5/95(2 min) =>5/95(1.5 min) => 90/10(1.0 min) => 90/10(0.5 min) U ZQ WAKOsil 3C18 AR,(Wako Room Temp. A) 0.05% TFA, H2O B) 0.05% 2.0 210-400 nm Pure ChemicalIndustries, TFA, MeCN PDA total Ltd.) 4.6 mm I.D. × 30 mm (A/B): 90/10=> 90/10(0.2 min) => 5/95(3.1 min) => 5/95(1.4 min) W ZMD Sunfire C18(Waters) Room Temp. A) 0.05% TFA, H2O B) 0.05% 4.0 200-400 nm 4.5 mmI.D. × 50 mm, 5 um TFA, MeCN PDA total (A/B): 90/10 => 5/95(3.5 min) =>90/10(1 min) => 90/10(0.5 min) Y ZMD Sunfire C18 (Waters) Room Temp. A)0.05% TFA, H2O B) 0.05% 2.0 210-400 nm 4.5 mm I.D. × 50 mm, 7 um TFA,MeCN PDA total (A/B): 90/10 => 0/100(3.5 min) => 0/100(1 min)

Microwave Reaction

The reaction was carried out by using a snap cap reaction vial togetherwith an Explorer™ (manufactured by CEM Microwave Technology) or aninitiator (manufactured by Biotage). Maximum output setting includescooling of the reaction vessel by air in order to avoid temperatureincrease caused by microwave irradiation.

Commercially available reagents were obtained and used without anyfurther purification. The room temperature indicates the temperaturerange of between about 20 to 25° C. All the non-aqueous reaction wascarried out in anhydrous solvent under nitrogen or argon atmosphere. Forconcentration under reduced pressure or removal of a solvent bydistillation, a rotary evaporator was used.

For preparing the compounds, when there is a possibility of having anundesirable side reaction, a functional group was protected using aprotecting group to produce a target molecule, and the protecting groupwas removed later, if desired. Selection, addition and removal of aprotecting group were carried out according to the method described inthe literature [Greene and Wuts, “Protective Groups in OrganicSynthesis” (4^(th) edition, John Wiley & Sons 2007)], for example.

Example 1 Compound A27-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

7-Methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 209 g, 1.18mol), tetrabutylammonium hydrogen sulfate (40 g, 0.118 mol) and methyliodide (162 g, 2.60 mol) were suspended in THF (500 ml) at roomtemperature. Under stirring, the mixture was added with 50% aqueoussolution of potassium hydroxide (400 g) over 5 min. Reflux occurred asthe inner temperature rapidly increases. Once the inner temperaturestopped to increase, stirring was continued for 45 min. The reactionsolution was diluted with distilled water (1 L) and extracted twice withCPME (1.5 L). The combined organic layer was washed (distilled water 1L×3), dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The resulting crude product was recrystallized withMeOH (1 L) and distilled water (500 ml) to obtain the title compound asa colorless needle-like crystal (177 g, 73%).

¹H-NMR (400 MHz, CDCl₃) δ 1.43 (6H, s), 2.65 (2H, t, 12 Hz), 3.02 (2H,t, 12 Hz), 3.79 (3H, s), 6.74 (1H, m), 6.87 (1H, m), 7.24 (1H, m).

LCMS: m/z 205 [M+H]⁺

Example 2 Compound A3-1, Compound A3-23-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole1-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole

7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,66.2 g, 324 mmol) and 3-bromophenylhydrazine hydrochloric acid salt(71.0 g, 318 mmol) were dissolved in AcOH (350 ml) and refluxed understirring for 6 hr. The reaction solvent was removed by distillationunder reduced pressure to obtain the crude product as a mixture of thetitle compound A3-1 and A3-2.

Example 3 Compound A43-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one

The crude product obtained from the above (i.e., mixture of A3-1 andA3-2) was dissolved in a mixture solvent of THF (450 ml) and distilledwater (50 ml), added once with DDQ (115 g, 509 mmol), and then stirredat room temperature for 1 hr. The reaction mixture was diluted with CPME3L, and the organic layer was washed three times with 0.5 N aqueoussolution of sodium hydroxide (1 L) and twice with distilled water (1 L)in order and dried over anhydrous sodium sulfate. The organic layer wasconcentrated to 500 ml under reduced pressure. The precipitated productwas collected by filtration and washed with a small amount of CPME toobtain the title compound as a yellow crystal (48 g, 40%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.73 (6H, s), 3.90 (3H, s), 7.06-7.09 (1H,m), 7.32-7.38 (2H, m), 7.65-7.66 (1H, m), 8.09-8.17 (2H, m), 12.32 (1H,br. s).

LCMS: m/z 370, 372 [M+H]⁺

Example 4 Compound AA14-Methoxy-2-(3-trimethylsilanylprop-2-ynyl)-benzoic Acid Methyl Ester

To the THF (16 ml) solution of 2-bromomethyl-4-methoxy-benzoic acidmethyl ester (961 mg, 4.09 mmol), triphenylphosphine (107 mg, 0.1 eq.),cesium carbonate (1.87 g, 1.4 eq.), copper iodide (59 mg, 0.076 eq.) andtris (dibenzylideneacetone) dipalladium (86 mg, 0.023 eq.) were added,degassed, flushed with nitrogen gas, added with trimethylsilylacetylene(734 μl, 1.3 eq.), and then stirred overnight at 55° C. To the reactionsolution, saturated aqueous solution of ammonium chloride was addedfollowed by extraction with ethyl acetate. The organic layer was washedwith brine and dried over magnesium sulfate. The drying agent wasremoved by filtration and the residues obtained after concentrationunder reduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (brown oilysubstance, 606 mg, 54%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.93 (1H, d, J=8.8 Hz), 7.33 (1H, d, J=2.6Hz), 6.78 (1H, dd, J=8.8, 2.6 Hz), 4.09 (2H, s), 3.86 (3H, s), 3.84 (3H,s), 0.14 (9H, s).

LCMS: m/z 277 [M+H]⁺

HPLC retention time: 3.30 min (analysis condition U)

Example 5 Compound AA22-(1,1-Dimethyl-3-trimethylsilanylprop-2-ynyl)-4-methoxy-benzoic AcidMethyl Ester

To the toluene (4 ml) solution of4-methoxy-2-(3-trimethylsilanyl-prop-2-ynyl)-benzoic acid methyl ester(Compound AA1, 273 mg, 0.988 mmol), sodium bis (trimethylsilyl) amide(2.1 ml, 1.9 m solution, 4 eq.) and iodomethane (308 μl, 5 eq.) wereadded at −78° C. After allowing the reaction temperature to increase tothe room temperature, the mixture was stirred for 2 hr. To the reactionsolution, saturated aqueous solution of ammonium chloride was addedfollowed by extraction with ethyl acetate. The organic layer was washedwith brine and dried over magnesium sulfate. The drying agent wasremoved by filtration and the residues obtained after concentrationunder reduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (yellow oilysubstance, 226 mg, 75%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.45 (1.0H, d, J=8.4 Hz), 7.09 (1.1H, d,J=2.6 Hz), 6.75 (1H, m), 3.84 (3H, s), 3.82 (3H, s), 1.70 (6H, s), 0.14(9H, s)

LCMS: m/z 305 [M+H]⁺

HPLC retention time: 3.38 min (analysis condition U)

Example 6 Compound AA3 2-(1,1-Dimethylprop-2-ynyl)-4-methoxy-benzoicAcid Methyl Ester

To the THF (18 ml) solution of2-(1,1-dimethyl-3-trimethylsilanylprop-2-ynyl)-4-methoxy-benzoic acidmethyl ester (Compound AA2, 912 mg, 3 mmol), tetrabutylammonium fluoride(2.061 g, 2.6 eq.) was added, and then stirred for 3 hr at roomtemperature. To the reaction solution, saturated aqueous solution ofammonium chloride was added followed by extraction with ethyl acetate.The organic layer was washed with brine and dried over magnesiumsulfate. The drying agent was removed by filtration and the residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (yellow oily substance, 524 mg, 75%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.44 (1H, d, J=8.4 Hz), 7.05 (1H, d, J=2.3Hz), 6.76 (1H, dd, J=8.4, 2.3 Hz), 3.84 (3H, s), 3.82 (3H, s), 1.73 (6H,s)

LCMS: m/z 223 [M+H]⁺

HPLC retention time: 2.55 min (analysis condition U)

Example 7 Compound AA42-[1-(6-Cyano-1-methanesulfonyl-1H-indol-2-yl)-1methylethyl]-4-methoxy-benzoicAcid Methyl Ester

To the DMF (2 ml) solution of2-(1,1-dimethylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester(Compound AA3, 134 mg, 0.577 mmol) andN-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound AA5, 167 mg, 1.05eq.), copper iodide (9 mg, 0.08 eq.) and TEA (129 μl, 1.6 eq.) wereadded, degassed and flushed with nitrogen gas, added with dicholorobis(triphenylphosphine) palladium (20 mg, 0.05 eq.), and then degassed andflushed again with nitrogen gas. After stirring for 2 hr at 90° C., thereaction solution was added with water, extracted with ethyl acetate.The organic layer was washed with an brine and dried over magnesiumsulfate. The drying agent was removed by filtration and the residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (white solid, 152 mg, 62%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.19 (1H, dd, J=0.6, 0.6 Hz), 7.84 (1H, dd,J=8.0, 0.6 Hz), 7.67 (1H, dd, J=8.0, 1.3 Hz), 7.13 (1H, d, J=8.4 Hz),6.99 (1H, s), 6.96 (1H, br. s), 6.85 (1H, dd, J=8.4, 2.5 Hz), 3.78 (3H,s), 3.12 (3H, s), 3.09 (3H, br. s), 1.89 (6H, s).

LCMS: m/z 427 [M+H]⁺

HPLC retention time: 2.77 min (analysis condition U)

Example 8 Compound AA5 N-(2-Bromo-5-cyanophenyl)methanesulfonamide

To a mixture of 3-amino-4-bromo-benzonitrile (1.98 g, 10 mmol), TEA(5.06 g, 50 mmol), and methylene chloride (50 ml), mesyl chloride (2.71ml, 35 mmol) was added at 0° C. and the mixture was stirred at roomtemperature for 30 min. Water was added to the reaction solution, whichwas then extracted with dichloromethane. The organic layer was driedover sodium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure were addedwith tetrahydrofuran (100 ml), water (400 μl) and sodium hydride (540mg, 15.5 mmol), and stirred at room temperature for 16 hr. To thereaction solution, saturated aqueous solution of ammonium chloride (200ml) was added followed by extraction with ethyl acetate. The organiclayer was dried over sodium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (hexane/ethylacetate) to obtain the title compound (2.48 g, 90%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.82 (1H, s), 7.87 (1H, d, J=4 Hz), 7.75(1H, d, J=8 Hz), 7.70 (1H, dd, J=8 Hz, 4 Hz), 3.14 (3H, s)

HPLC retention time: 1.63 min (analysis condition U)

Example 9 Compound AA62-(1-Hydroxy-1-methylethyl)-1H-indole-6-carbonitrile

To N-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound AA5, 230 mg, 1mmol), 3-methyl-2-butyn-3-ol (0.15 ml, 1.5 mmol), X-Phos (72 mg, 15%mol), PdCl₂(CH₃CN)₂ (13 mg, 5% mol) and cesium carbonate (390 mg, 2mmol), DMA (2 ml) was added, and the mixture was stirred at 100° C. for3 hr. Water and 5 N hydrochloric acid solution were added to thereaction solution, which was then extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate. The drying agent wasremoved by filtration and the residues obtained after concentrationunder reduced pressure were purified by silica gel column chromatography(hexane/ethyl acetate) to obtain the title compound (130 mg, 75%).

¹H-NMR (400 MHz, CDCl₃) δ: 8.76 (1H, s), 7.68 (1H, s), 7.60 (1H, d, J=8Hz), 7.32 (1H, dd, J=8 Hz, 4 Hz), 6.37 (1H, m), 1.93 (1H, s), 1.70 (6H,s)

LCMS: m/z 201 [M+H]⁺

HPLC retention time: 2.12 min (analysis condition U)

Example 10 Compound A5-13-Bromo-8-hydroxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A6,the title compound was synthesized from Compound A4.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.30 (1H, s), 10.21 (1H, s), 8.06-8.11(1H, m), 8.01-8.05 (1H, m), 7.62-7.66 (1H, m), 7.32-7.37 (1H, m),7.08-7.12 (1H, m), 6.84-6.90 (1H, m), 1.69 (6H, s).

LCMS: m/z 356, 358 [M+H]⁺

HPLC retention time: 2.30 min (analysis condition U)

Example 11 Compound A5-28-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

(Method 1)3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one(Compound A4, 10.45 g, 28.2 mmol) and copper (I) cyanide (5.0 g, 50.2mmol) were dissolved in NMP (100 ml), followed by stirring at 170° C.for 17 hr. The reaction mixture was suspended in ethyl acetate (500 mL)and distilled water (200 mL). The insoluble matters were removed byCelite filtration and washed twice with ethyl acetate (300 mL×2). Theorganic layer was washed once with an aqueous solution of disodium EDTA(200 mL) and twice with saturated brine (200 mL) in order, and driedover anhydrous sodium sulfate. The organic layer was concentrated underreduced pressure to yield a product, which was suspended and washed witha small amount of CPME to obtain the title compound as a colorlesscrystal (6.58 g, 73%).

(Method 2) To the THF (5.6 ml) solution of2-[1-(6-cyano-1-methanesulfonyl-1H-indol-2-yl)-1-methylethyl]-4-methoxy-benzoicacid methyl ester (Compound AA4, 138 mg, 0.324 mmol), tetrabutylammoniumfluoride (514 mg, 6 eq.) was added, and the mixture was stirred at roomtemperature overnight. Thereafter, 2 M aqueous solution of sodiumhydroxide (5.6 ml) was added to the mixture, which was then stirred for4 hr, added with 1 M HCl, and extracted with ethyl acetate. The organiclayer was washed with brine and dried over magnesium sulfate. The dryingagent was removed by filtration and the residues obtained afterconcentration under reduced pressure were dissolved in ethyl acetate (10ml) and added with e 4 M HCl and ethyl acetate solution (10 ml) followedby stirring at room temperature for 30 min. The residues obtained afterconcentration of the reaction solution under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (89.2 mg, 62%).

(Method 3) To nitrobenzene (5 ml) and aluminum chloride (400 mg, 3mmol), 4-methoxybenzoyl chloride (400 mg, 2.3 mmol) was added. Afterstirring for 30 min at room temperature,2-(1-hydroxy-1-methyl-ethyl)-1H-indole-6-carbonitrile (Compound AA6, 200mg, 1 mmol) was added followed by stirring at room temperature for 3 hr.Water was added to the reaction solution, which was then extracted withethyl acetate. The organic layer was dried over sodium sulfate. Thedrying agent was removed by filtration and the residues obtained afterconcentration under reduced pressure were purified by silica gel columnchromatography (hexane/ethyl acetate) to obtain the title compound (127mg, 40%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.71 (6H, s), 3.89 (3H, s), 7.07-7.09 (1H,m), 7.34 (1H, s), 7.58-7.60 (1H, m), 7.99 (1H, s), 8.14-8.16 (1H, m),8.30-8.32 (1H, m), 12.32 (1H, br. s),

LCMS: m/z 317 [M+H]⁺

HPLC retention time: 2.56 min (analysis condition U)

Example 12 Compound A68-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A5-2, 6.58 g, 20.8 mmol) was dissolved in pyridinehydrochloric acid salt (25.0 g), and stirred at 170° C. for 13 hr. Thereaction mixture was partitioned in ethyl acetate (400 mL) and distilledwater (400 mL), and the aqueous layer was extracted one more time withethyl acetate (400 mL). The combined organic layer was washed twice withdistilled water (100 mL) and once with saturated brine (100 mL) inorder, and dried over anhydrous sodium sulfate. The organic layer wasconcentrated under reduced pressure to yield a product, which wassuspended and washed with a small amount of CPME to obtain the titlecompound as a colorless crystal (5.91 g, 93%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.73 (6H, s), 6.87-6.90 (1H, m), 7.11 (1H,s), 7.57-7.59 (1H, m), 7.97 (1H, s), 8.04-8.06 (1H, m), 8.29-8.31 (1H,m), 10.27 (1H, s), 12.66 (1H, br. s),

LCMS: m/z 303 [M+H]⁺

Example 13 Compound A7-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylicAcid Tert-Butyl Ester

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A6, 30 mg, 0.099 mmol) was dissolved in THF (1 mL), added with4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 2 eq.),triphenylphosphine (52 mg, 2 eq.), and diisopropyl azodicarboxlyate (43μL, 2 eq.) in order, and stirred at room temperature for 4 hr. Thereaction solution was poured to water, and then extracted with ethylacetate. The organic layer was washed with saturated brine and driedover sodium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (37 mg, 76%).

¹H-NMR (400 MHz, CDCl₃) δ: 9.44 (1H, s), 8.77 (1H, d, J=7.8 Hz), 8.62(1H, d, J=8.2 Hz), 8.00 (1H, s), 7.81 (1H, d, J=8.2 Hz), 7.34 (1H, s),7.26 (1H, d, J=7.8 Hz), 4.85-4.93 (1H, m), 3.96-4.04 (2H, m), 3.60-3.70(2H, m), 2.19-2.32 (2H, m), 1.89-2.15 (8H, m), 1.74 (9H, s)

LCMS: m/z 430 [M+H]⁺

HPLC retention time: 4.09 min (analysis condition W)

Example 14 Compound A7-26,6-Dimethyl-11-oxo-8-[2-(2-oxo-imidazolidin-1-yl)-ethoxy]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and1-(2-hydroxy-ethyl)-imidazolidin-2-one.

LCMS: m/z 415 [M+H]⁺

HPLC retention time: 2.96 min (analysis condition W)

Example 15 Compound A7-3[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-carbamicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and(2-hydroxy-ethyl)-carbamic acid tert-butyl ester.

LCMS: m/z 346 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition W)

Example 16 Compound A7-46,6-Dimethyl-8-(2-methylsulfanyl-ethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and2-methylthioethanol.

LCMS: m/z 451 [M+H]⁺

HPLC retention time: 4.23 min (analysis condition W)

Example 17 Compound A7-56,6-Dimethyl-8-(2-methylsulfanyl-ethoxy)-5-(2-methylsulfanyl-ethyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound A7-4.

LCMS: m/z 377 [M+H]⁺

HPLC retention time: 3.75 min (analysis condition W)

Example 18 Compound A7-66,6-Dimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 andtetrahydropyran-4-ol.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.72 (1H, br. s), 8.32 (1H, d, 8.5 H z),8.15 (1H, d, 8.5 Hz), 8.01 (1H, s), 7.61 (1H, d, 8.5 Hz), 7.38 (1H, s),7.15 (1H, d, 8.5 Hz), 4.86-4.81 (1H, m), 3.93-3.88 (2H, m), 3.58-3.52(2H, m), 2.06-2.00 (2H, m), 1.85 (6H, s), 1.69-1.60 (2H, m)

LCMS: m/z 387 [M+H]⁺

HPLC retention time: 3.47 min (analysis condition W)

Example 19 Compound A7-76,6-Dimethyl-11-oxo-8-(pyridin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 andpyridin-4-yl-methanol.

LCMS: m/z 394 [M+H]⁺

HPLC retention time: 2.56 min (analysis condition W)

Example 20 Compound A7-88-(2-Methoxyethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and 2-methoxyethanol.

¹H-NMR (400 MHz, DMSO-d₆) δ: 11.69 (1H, br. s), 8.27 (1H, d, 7.9 Hz),8.10 (1H, d, 8.5 Hz), 7.95 (1H, s), 7.55 (1H, d, 7.9 Hz), 7.32 (1H, d,2.4 Hz), 7.05 (1 H, d, 8.5 Hz), 4.22 (2H, t, 4.3 Hz), 3.67 (2H, t, 4.3Hz), 1.72 (6H, s)

LCMS: m/z 361 [M+H]⁺

HPLC retention time: 3.38 min (analysis condition W)

Example 21 Compound A7-98-[2-(2-Methoxyethoxy)ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and2-(2-methoxyethoxy)ethanol.

LCMS: m/z 405 [M+H]⁺

HPLC retention time: 3.32 min (analysis condition W)

Example 22 Compound A7-106,6-Dimethyl-8-(3-methyloxetan-3-ylmethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and3-chloromethyl-3-methyloxetane.

LCMS: m/z 387 [M+H]⁺

HPLC retention time: 2.23 min (analysis condition S)

Example 23 Compound A7-11-1[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)ethyl]ethyl-carbamic Acid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 andethyl-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester.

LCMS: m/z 474 [M+H]⁺

HPLC retention time: 2.93 min (analysis condition U)

Example 24 Compound A7-11-28-(2-Ethylaminoethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound A7-11-1.

LCMS: m/z 374 [M+H]⁺

HPLC retention time: 1.35 min (analysis condition U)

Example 25 Compound A7-128-(2-Hydroxyethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and 2-bromo-ethanol.

LCMS: m/z 437 [M+H]⁺

HPLC retention time: 2.93 min (analysis condition U)

Example 26 Compound A7-13-16,6-Dimethyl-11-oxo-8-(2-phenyl-[1,3]dioxan-5-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and2-phenyl-[1,3]dioxan-5-ol.

LCMS: m/z 465 [M+H]⁺

HPLC retention time: 4.10 min (analysis condition W)

Example 27 Compound A7-13-28-(2-Hydroxy-1-hydroxymethylethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Anhydrous ferric trichloride (56 mg, 5 eq.) was added to thedichloromethane (2 mL) suspension of6,6-dimethyl-11-oxo-8-(2-phenyl-[1,3]dioxan-5-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A7-13-1, 13 mg, 0.028 mmol), and stirred at room temperaturefor 1 hr. The reaction solution was added to water, and then extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over sodium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by high performance liquid chromatography toobtain the title compound (7 mg, 46%).

LCMS: m/z 377 [M+H]⁺

HPLC retention time: 2.70 min (analysis condition W)

Example 28 Compound A7-14-18-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and toluene-4-sulfonicacid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester.

LCMS: m/z 417 [M+H]⁺

HPLC retention time: 3.47 min (analysis condition Y)

Example 29 Compound A7-14-28-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the solution of THF and water (4:1, 1 mL) of8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A14-1, 30 mg, 0.07 mmol), camphor sulfonic acid (36 mg, 0.14mmol) was added at room temperature. After stirring at room temperaturefor 38 hr, the mixture was extracted with ethyl acetate. The organiclayer was dried over sodium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography(dichloromethane/methanol) to obtain the title compound (white solid, 28mg, 72%).

¹H-NMR (300 MHz, DMSO-d₆) σppm; 12.7 (s, 1H), 8.31 (d, 1H, J=8.01 Hz),8.15 (d, 1H, J=8.77 Hz), 8.00 (s, 1H), 7.60 (d, 1H, J=8.01 Hz), 7.12 (s,1H), 7.09 (d, 1H, J=8.77 Hz), 4.46 (m, 1H), 4.15 (m, 3H), 3.78 (m, 1H),1.76 (s, 6H), 1.38 (s, 3H), 1.32 (s, 3H)

LCMS: m/z 377 [M+H]⁺

HPLC retention time: 1.80 min (analysis condition U)

Example 30 Compound A7-14-38-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-4,the title compound was prepared as a crude product from CompoundA7-14-1.

Example 31 Compound A7-14-48-((R)-2,3-Dihydroxy-propoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound A7-14-3 (303 mg,98%).

LCMS: m/z 484 [M+H]⁺

HPLC retention time: 2.08 min (analysis condition D)

Example 32 Compound A7-15-18-[(4R,5S)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol.

LCMS: m/z 516 [M+H]⁺

HPLC retention time: 3.97 min (analysis condition Y)

Example 33 Compound A7-15-26,6-Dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound A7-15-1.

LCMS: m/z 407 [M+H]⁺

HPLC retention time: 1.73 min (analysis condition U)

Example 34 Compound A7-166,6-Dimethyl-8-(1-methyl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and1-methylpiperidin-4-ol.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.75 (1H, s), 8.32 (1H, d, J=7.9 Hz), 8.14(1H, d, J=9.8 Hz), 8.00 (1H, s), 7.60 (1H, d, J=7.9 Hz), 7.34 (1H, s),7.11 (1H, d, J=9.1 Hz), 4.62 (1H, m), 2.64 (2H, m), 2.23 (2H, m), 2.21(s, 3H), 1.99 (2H, m), 1.77 (s, 6H), 1.73 (2H, m).

LCMS: m/z 400 [M+H]⁺

HPLC retention time: 1.42 min (analysis condition S)

Example 35 Compound A7-178-(2-Diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A6, 25 mg, 0.083 mmol) was dissolved in N,N-dimethylacetamide(1 mL), added with 2-chloroethyldiethylamine (16 mg, 1.1 eq.) and cesiumcarbonate (54 mg, 2 eq.) in order and stirred at 100° C. for 4 hr. Thereaction solution was poured over water and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover sodium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure werepurified by amino silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (11 mg, 32%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.32 (1H, d, J=8.2 Hz), 8.15 (1H, d, J=8.7Hz), 8.01 (1H, s), 7.61 (1H, d, J=8.2 Hz), 7.35 (1H, d, J=1.8 Hz), 7.09(1H, dd, J=8.7, 1.8 Hz), 4.19 (2H, t, J=5.9 Hz), 2.83 (2H, t, J=5.9 Hz),2.58 (4H, q, J=7.0 Hz), 1.78 (6H, s), 1.00 (6H, t, J=7.0 Hz)

LCMS: m/z 402 [M+H]⁺

HPLC retention time: 2.52 min (analysis condition W)

Example 36 Compound A7-18N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-acetamide

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and2-chloroethylacetamide.

LCMS: m/z 388 [M+H]⁺

HPLC retention time: 2.91 min (analysis condition W)

Example 37 Compound A7-19[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-carbamicAcid Ethyl Ester

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 andethyl-2-chloroethylcarbamate.

LCMS: m/z 418 [M+H]⁺

HPLC retention time: 3.35 min (analysis condition W)

Example 38 Compound A7-20[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-urea

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and 2-chloroethylurea.

LCMS: m/z 399 [M+H]⁺

HPLC retention time: 2.80 min (analysis condition W)

Example 39 Compound A7-216,6-Dimethyl-8-(oxetan-3-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and toluene-4-sulfonicacid oxetan-3-yl ester.

LCMS: m/z 359 [M+H]⁺

HPLC retention time: 2.00 min (analysis condition S)

Example 40 Compound A7-226,6-Dimethyl-11-oxo-8-(pyrimidin-2-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and 2-bromopyrimidine.

LCMS: m/z 381 [M+H]⁺

HPLC retention time: 2.00 min (analysis condition S)

Example 41 Compound A7-23(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethylAcetate Ester

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and 3-chloro-propionicacid ethyl ester.

LCMS: m/z 389 [M+H]⁺

HPLC retention time: 3.37 min (analysis condition U)

Example 42 Compound A7-248-(2-Bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and 2-bromoethanol.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.75 (1H, br. s), 8.32 (1H, d, J=8.2 Hz),8.17 (1H, d, J=8.6 Hz), 8.01 (1H, s), 7.61 (1H, dd, J=8.2, 1.4 Hz), 7.40(1H, d, J=2.2 Hz), 7.12 (1H, dd, J=8.6, 2.2 Hz), 4.50 (2H, t, J=5.3 Hz),3.88 (2H, t, J=5.3 Hz), 1.77 (6H, s).

LCMS: m/z 409, 411 [M+H]⁺

HPLC retention time: 2.48 min (analysis condition S)

Example 43 Compound A7-256,6-Dimethyl-11-oxo-8-(piperidin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrileHydrochloric Acid Salt

Under nitrogen atmosphere,3-cyano-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound A6, 85 mg, 0.28 mmol) and triphenylphosphine (150 mg, 2 eq.)were added with THF (2 ml), and then further added dropwise with4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, 2eq.) and 2.19 N toluene solution of diethyl azodicarboxylic acid (0.26mL, 2 eq.). The resultant was stirred at room temperature for 12 hrunder nitrogen atmosphere. The residues obtained after concentrating thereaction solution under reduced pressure were purified by silica gelcolumn chromatography (ethyl acetate/dichloromethane) to obtain4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxymethyl)-piperidine-1-carboxylicacid tert-butyl ester (white powder, 120 mg).

To the resulting compound, 4 N hydrochloric acid and dioxane solutionwas added under cooling. After stirring at room temperature for 2 hr,the solvent was removed under nitrogen stream. Then, the residues werewashed with diethyl ether and then subjected to azeotropic treatmentwith toluene, followed by drying under vacuum and filtration to obtainthe title compound (79 mg).

LCMS: m/z 399 [M+H]⁺

HPLC retention time: 2.22 min (analysis condition C)

Example 44 Compound A8-16,6-Dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

THF (0.5 mL) and TFA (0.5 mL) were added to4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylicacid tert-butyl ester (Compound A7-1, 35 mg, 0.072 mmol), and themixture was stirred at room temperature until Compound A7-1 disappears.The reaction solution was concentrated under reduced pressure and theresidue was desalinated by using anion exchanger PL StratoSpheres(trademark) PL-HCO3 MP to obtain the title compound (37 mg, 76%).

¹H-NMR (400 MHz, CD₃OD) δ: 8.38 (1H, d, J=7.9 Hz), 8.24 (1H, d, J=8.5Hz), 7.85 (1H, s), 7.53 (1H, d, J=7.9 Hz), 7.27 (1H, s), 7.09 (1H, d,J=8.5 Hz), 4. 67-4.76 (1H, m), 3.07-3.20 (2H, m), 2.77-2.87 (2H, m),2.03-2.15 (2H, m), 1.80 (6H, s), 1.69-1.77 (2H, m)

LCMS: m/z 386 [M+H]⁺

HPLC retention time: 2.51 min (analysis condition W)

Example 45 Compound A8-28-(2-Amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound A7-3.

LCMS: m/z 346 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition W)

Example 46 Compound A8-38-(2-Methanesulfonyl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8,the title compound was prepared from Compound A7-5.

LCMS: m/z 409 [M+H]⁺

HPLC retention time: 3.13 min (analysis condition W)

Example 47 Compound A8-48-(2-Methanesulfinyl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound A8-3.

LCMS: m/z 393 [M+H]⁺

HPLC retention time: 2.87 min (analysis condition W)

Example 48 Compound A8-55,6,6-Trimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A10-1,the title compound was prepared from Compound A7-6.

LCMS: m/z 401 [M+H]⁺

HPLC retention time: 2.72 min (analysis condition S)

Example 49 Compound A8-6-12-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A5-2, 50 mg, 0.158 mmol) was dissolved in CH₃CN (1 mL), addedwith NBS (56 mg, 2 eq.), and stirred at 80° C. overnight. The reactionsolution was added to water, and then extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over sodiumsulfate. The drying agent was removed by filtration and the residuesobtained after concentration under reduced pressure were added with MeOHand the solid remained after dissolution was filtered to obtain thetarget compound (yellow powder, 20 mg, 38%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.92 (1H, s), 8.50 (1H, s), 8.16 (1H, d,J=8.5 Hz), 8.14 (1H, s), 7.36 (1H, d, J=2.4 Hz), 7.11 (1H, dd, J=8.5,2.4 Hz), 3.92 (3H, s), 1.78 (6H, s).

LCMS: m/z 395, 397 [M+H]⁺

HPLC retention time: 2.57 min (analysis condition S)

Example 50 Compound A8-6-22-Bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound A8-6-1.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.46 (1H, s), 8.10 (1H, s), 8.05 (1H, d,J=8.6 Hz), 7.13 (1H, d, J=2.1 Hz), 6.89 (1H, dd, J=8.5, 2.1 Hz), 1.71(6H, s).

LCMS: m/z 381,383 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition S)

Example 51 Compound A8-6-32-Bromo-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A8-6-2.

¹H-NMR (400 MHz, CD₃OD) δ: 8.53 (1H, d, J=0.5 Hz), 8.20 (1H, d, J=8.7Hz), 7.88 (1H, d, J=0.5 Hz), 7.28 (1H, d, J=2.3 Hz), 7.05 (1H, dd,J=8.9, 2.5 Hz), 4.24 (2H, t, J=5.7 Hz), 2.96 (2H, t, J=5.7 Hz), 2.70(4H, q, J=7.1 Hz), 1.79 (6H, s), 1.12 (6H, t, J=7.2 Hz).

LCMS: m/z 480, 482 [M+H]⁺

HPLC retention time: 1.73 min (analysis condition S)

Example 52 Compound A8-7(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-aceticAcid

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethylacetate ester (Compound A7-23, 180 mg, 0.464 mmol) and potassiumhydroxide (130 mg, 2.32 mmol) were dissolved in THF (10 ml) and water(1.8 mL), and stirred at 70° C. for 2 hr. After cooling to roomtemperature, the mixture was extracted with dichloromethane. Water layer(

) was adjusted to be acidic by using 1 N hydrochloric acid, and theprecipitated solid was filtered and washed several times with water toobtain the title compound (white solid, 130 mg, 78%).

¹H-NMR (300 MHz, DMSO) σppm 13.09 (s, 1H), 8.31 (d, 1H, J=8.1 Hz), 8.11(d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.25 (d, 1H,J=2.1 Hz), 6.97 (d, 1H, J=8.4 Hz), 4.51 (s, 2H), 1.73 (s, 6H)

LCMS: m/z 361 [M+H]⁺

HPLC retention time: 2.97 min (analysis condition U)

Example 53 Compound A8-86,6-Dimethyl-8-(2-morpholin-4-yl-ethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17,the title compound was prepared from Compound A7-24 and morpholine.

¹H-NMR (500 MHz, CD₃OD+CDCl₃) σ ppm; 8.4 (d, 1H, J=8.2 Hz), 8.3 (d, 1H,J=8.7 Hz), 7.8 (s, 1H), 7.5 (dd, 1H, J=1.1 Hz, J=8.2 Hz), 7.2 (d, 1H,J=2.3 Hz), 7.0 (dd, 1H, J=2.2 Hz, J=8.7 Hz), 4.2 (t, 2H, J=5.3 Hz), 3.7(t, 4H, J=4.5 Hz), 2.9 (t, 2H, J=5.3 Hz), 2.6 (t, 4H, J=4.5 Hz), 1.8 (s,6H)

LCMS: m/z 416 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition U)

Example 54 Compound A8-98-[2-(1,1-Dioxothiomorpholino)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A7-24 andthiomorpholine-1,1-dioxide.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.72 (1H, s), 8.31 (1H, d, 8.5 Hz), 8.15(1H, d, 8.5 Hz), 8.00 (1H, s), 7.60 (1H, d, 8.5 Hz), 7.36 (1H, d, 1.8Hz), 7.10 (1H, dd, 1.8, 8.5), 4.25 (2H, t, 5.5 Hz), 3.06-3.33 (8H, m),2.97 (2H, t, 5.5), 1.77 (6H, s)

LCMS: m/z 464 [M+H]⁺

HPLC retention time: 2.70 min (analysis condition W)

Example 55 Compound A8-108-(2-Tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A7-24 and tert-butylamine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.71 (1H, s), 8.32 (1H, d, 7.9 Hz), 8.15(1H, d, 9.1 Hz), 8.07 (1 d, 1.8 Hz), 7.60 (1H, dd, 1.8, 7.9 Hz), 7.35(1H, d, 2.4 Hz), 7.09 (1H, dd, 2.4, 9.1 Hz), 4.16 (2H, t, 6.1 Hz), 2.91(2H, t, 6.1 Hz), 1.77 (6H, s), 1.08 (9H, s)

LCMS: m/z 402 [M+H]⁺

HPLC retention time: 2.55 min (analysis condition W)

Example 56 Compound A8-118-(2-Sec-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17,the title compound was prepared from Compound A7-24 and sec-butylamine.

LCMS: m/z 402 [M+H]⁺

HPLC retention time: 1.88 min (analysis condition U)

Example 57 Compound A8-128-[2-(2-Hydroxy-1,1-dimethyl-ethylamino)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17,the title compound was prepared from Compound A7-24 and2-amino-2-methyl-propan-1-ol.

¹H-NMR (300 MHz, DMSO-d₆) σppm; 12.65 (brs, 1H), 8.31 (d, 1H, J=8.0 Hz),8.15 (d, 1H, J=8.8 Hz), 7.99 (s, 1H), 7.59 (d, 1H, J=8.0 Hz), 7.34 (d,1H, J=2.3 Hz), 7.08 (dd, 1H, J=2.2 Hz, J=8.8 Hz), 4.58 (brs, 1H), 4.16(t, 2H, J=5.7 Hz), 3.20 (s, 2H), 2.88 (t, 2H, J=5.7 Hz), 1.76 (s, 6H),0.97 (s, 6H)

LCMS: m/z 418 [M+H]⁺

HPLC retention time: 2.47 min (analysis condition U)

Example 58 Compound A8-138-[2-(4-Ethyl-piperazin-1-yl)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17,the title compound was prepared from Compound A7-24 and1-ethyl-piperazine.

LCMS: m/z 443 [M+H]⁺

HPLC retention time: 1.68 min (analysis condition U)

Example 59 Compound A8-148-(2-Imidazol-1-yl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A6 and2-imidazol-1-yl-ethanol.

¹H-NMR (300 MHz, DMSO-d₆) σ ppm; 12.71 (s, 1H), 8.31 (d, 1H, J=8.3 Hz),8.14 (d, 1H, J=8.8 Hz), 7.99 (s, 1H), 7.73 (s, 1H), 7.60 (d, 1H, J=8.3Hz), 7.34 (s, 1H), 7.29 (s, 1H), 7.09 (d, 1H, J=8.8 Hz), 6.91 (s, 1H),4.20 (s, 4H), 1.76 (s, 6H)

LCMS: m/z 387 [M+H]⁺

HPLC retention time: 1.77 min (analysis condition U)

Example 60 Compound A8-158-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethoxy}-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound A7-24 and2-(2-hydroxy-ethylamino)-ethanol.

LCMS: m/z 434 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition U)

Example 61 Compound A8-161-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-piperidine-4-carboxylicAcid Amide

Under the same conditions as the method for synthesizing Compound A8-17,the title compound was prepared from Compound A7-24 andpiperidine-4-carboxylic acid amide.

LCMS: m/z 457 [M+H]⁺

HPLC retention time: 1.28 min (analysis condition S)

Example 62 Compound A8-176,6-Dimethyl-11-oxo-8-[2-(3-oxo-piperazin-1-yl)-ethoxy]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To DMF solution (5 mL) of8-(2-bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A7-24, 30 mg, 0.07 mmol), piperazin-2-one (44.9 mg, 0.35 mmol)and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) were added at roomtemperature and stirred at 80° C. for 18 hr. After cooling to roomtemperature, the mixture was extracted with ethyl acetate washed withsaturated brine. The organic layer was dried over magnesium sulfate. Thedrying agent was removed by filtration and the residues obtained afterconcentration under reduced pressure were purified by preparative TLC(dichloromethane/methanol) to obtain the title compound (white solid, 24mg, 80%).

¹H-NMR (300 MHz, DMSO-d₆) σppm; 12.71 (s, 1H), 8.32 (d, 1H, J=8.4 Hz),8.15 (d, 1H, J=8.8 Hz), 8.00 (s, 1H), 7.75 (s, 1H), 7.60 (d, 1H, J=8.4Hz), 7.37 (d, 1H, J=2.3 Hz), 7.09 (dd, 1H, J=2.3 Hz, J=8.8 Hz), 4.27 (t,2H, J=5.7 Hz), 3.19 (m, 2H), 3.08 (s, 2H), 2.83 (t, 2H, J=5.7 Hz), 2.70(t, 2H, J=5.7 Hz), 1.8 (s, 6H)

LCMS: m/z 429 [M+H]⁺

HPLC retention time: 1.29 min (analysis condition S)

Example 63 Compound A8-18 Morpholine-4-sulfonicacid[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-amide

The title compound was obtained as a by-product of the synthesis ofCompound C₁₋₂.

LCMS: m/z 495 [M+H]⁺

HPLC retention time: 2.00 min (analysis condition S)

Example 64 Compound A8-19 4-Methyl-piperazine-1-sulfonic acid[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-amide

The title compound was obtained as a by-product of the synthesis ofCompound C1-4.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.77 (6H, s), 2.16 (3H, s), 2.34 (4H, m),3.08 (4H, m), 3.35 (2H, m), 4.19 (2H, t, 5.34 Hz), 7.09 (1H, dd, 8.77Hz, 2.99 Hz), 7.37 (1H, bs, 1.91 Hz), 7.59 (2H, m), 8.01 (1H, s), 8.16(1H, d, 8.40 Hz), 8.32 (1H, d, 8.01 Hz), 12.7 (1H, s).

LCMS: m/z 501 [M+H]⁺

HPLC retention time: 1.43 min (analysis condition S)

Example 65 Compound A8-206,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-ylmethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6,6-Dimethyl-11-oxo-8-(piperidin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilehydrochloric acid salt (Compound A7-25, 30 mg, 0.075 mmol) andoxetan-3-one (38 mg, 7 eq.) were dissolved in acetic acid (0.2 ml), THF(1 ml) and methanol (1 ml), added with sodium cyanoborohydride (33 mg, 7eq.) at room temperature, and stirred overnight. The reaction solutionwas added with water, and then extracted with ethyl acetate. Thesolution was dried over sodium sulfate and the solvent was removed undervacuum and the resulting residues were purified by preparative TLC(chloroform: 2 N ammonia methanol=9:1) to obtain the target compound (15mg).

LCMS: m/z 456 [M+H]⁺

HPLC retention time: 2.78 min (analysis condition C)

Example 66 Compound A8-216,6-Dimethyl-8-[2-(1-oxetan-3-yl-piperidin-4-yl)-ethoxy]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-25,and Compound A8-20, the title compound was prepared from Compound A6 and4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (15mg).

LCMS: m/z 470 [M+H]⁺

HPLC retention time: 2.85 min (analysis condition C)

Example 67 Compound A9-1N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-methanesulfonamide

Trifluoroacetic acid salt of8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A8-2, 19 mg, 0.044 mmol) was suspended in dichloromethane (0.5mL), added with diisopropylethylamine (0.0157 mL, 2 eq.) andmethanesulfonyl chloride (0.0034 mL, 1 eq.), and then stirred at roomtemperature for 2 hr. The reaction solution was added to water, and thenextracted with dichloromethane. After washing with saturated brine, theorganic layer was dried over sodium sulfate. The drying agent wasremoved by filtration and the residues obtained after concentrationunder reduced pressure were separated by silica gel preparative TLC(ethyl acetate 100%) to obtain the target compound (5.5 mg, 29%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.47 (1H, d, J=8.2 Hz), 8.32 (1H, d, J=8.7Hz), 8.16 (1H, s), 7.76 (1H, d, J=8.2 Hz), 7.53-7.46 (2H, m), 7.26 (1H,d, J=8.7 Hz), 4.39-4.33 (2H, m), 3.58-3.51 (2H, m), 3.12 (3H, s), 1.93(6H, s)

LCMS: m/z 424 [M+H]⁺

HPLC retention time: 3.10 min (analysis condition W)

Example 68 Compound A9-2N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-2,2,2-trifluoro-acetamide

The title compound was obtained as a by-product of the synthesis ofCompound A9-1.

LCMS: m/z 442 [M+H]⁺

HPLC retention time: 3.45 min (analysis condition W)

Example 69 Compound A9-3-18-{2-(Tert-butyloxycarbonylaminosulfonyl)amino-ethoxy}-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Trifluoroacetic acid salt of8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A8-2, 20 mg, 0.044 mmol) was dissolved in pyridine (0.5 mL),added with N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-yl sulfonyl]azanide (13.5 mg, 1eq.), and then stirred at room temperature for 14 hr. The reactionsolution was added to water, and then extracted with ethyl acetate.After washing with saturated brine, the organic layer was dried oversodium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure wereseparated by silica gel preparative TLC(ethyl acetate) to obtain thetitle compound (16.1 mg, 68%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.74 (1H, s), 10.94 (1H, s), 8.33 (1H, d,J=8.5 Hz), 8.16 (1H, d, J=9.1 Hz), 8.02 (1H, s), 7.84 (1H, br. s), 7.62(1H, d, J=7.9 Hz), 7.36 (1H, s), 7.10 (1H, d, J=7.9 Hz). 4.24-4.18 (2H,m), 1.78 (6H, s), 1.32 (9H, s)

LCMS: m/z 525 [M+H]⁺

HPLC retention time: 3.48 min (analysis condition W)

Example 70 Compound A9-3-28-{2-(Methylaminosulfonyl)amino-ethoxy}-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound A9-3-1.

LCMS: m/z 425 [M+H]⁺

HPLC retention time: 2.95 min (analysis condition W)

Example 71 Compound A9-48-(1-Methanesulfonyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound A8-1 andmethanesulfonyl chloride.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.72 (1H, s), 8.30 (1H, d, J=8.5 Hz), 8.14(1H, d, J=8.5 Hz), 8.00 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.38 (1H, s),7.13 (1H, d, J=8.5 Hz), 4.81 (1H, s), 3.39-3.38 (2H, m), 3.19-3.13 (2H,m), 2.93 (3H, s), 2.11-2.04 (2H, m), 1.83-1.75 (8H, m).

LCMS: m/z 464 [M+H]⁺

HPLC retention time: 3.41 min (analysis condition U)

Example 72 Compound A9-58-[1-(2-Methoxy-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound A8-1 and1-bromo-2-methoxy-ethane.

¹H-NMR (400 MHz, CDCl₃) δ: 8.48-8.53 (1H, m), 8.32-8.38 (1H, m),7.74-7.77 (1H, m), 7.50-7.55 (1H, m), 7.07-7.10 (1H, m), 6.95-7.00 (1H,m), 4.43-4.51 (1H, m), 3.53 (2H, t, J=5.6 Hz), 3.36 (3H, s), 2.77-2.87(2H, m), 2.62 (2H, t, J=5.6 Hz), 2.35-2.47 (2H, m), 2.02-2.12 (2H, m),1.78-1.95 (2H, m), 1.82 (6H, s).

LCMS: m/z 444 [M+H]⁺

HPLC retention time: 2.00 min (analysis condition U)

Example 73 Compound A9-6-28-[1-(2-Hydroxy-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound A8-1 and(2-bromoethoxy)-tert-butyldimethylsilane, followed by treatment withtetrabutylammonium fluoride.

LCMS: m/z 430 [M+H]⁺

HPLC retention time: 1.45 min (analysis condition S)

Example 74 Compound A9-78-[1-(2-Fluoro-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound A8-1 andmethanesulfonic acid 2-fluoroethyl ester.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.67 (2H, m), 1.76 (6H, s), 2.01 (2H, m),2.37 (2H, t, 11.0 Hz), 2.61 (1H, t, 4.20 Hz), 2.70 (1H, t, 4.58), 2.78(2H, m), 4.46 (1H, t, 4.58 Hz), 4.62 (2H, t, 5.34 Hz), 7.10 (1H, dd,9.16 Hz, 2.29 Hz), 7.34 (1H, bs, 1.53 Hz), 7.60 (1H, dd, 8.40 Hz, 1.53Hz), 7.99 (1H, s), 8.13 (1H, d, 8.39 Hz), 8.30 (1H, d, 8.39 Hz), 12.7(1H, s).

LCMS: m/z 432 [M+H]⁺

HPLC retention time: 1.52 min (analysis condition S)

Example 75 Compound A9-88-(1-Acetyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound A8-1 and acetylchloride.

LCMS: m/z 428 [M+H]⁺

HPLC retention time: 1.91 min (analysis condition S)

Example 76 Compound A9-92-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetamide

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A6 and 2-bromo-acetamide.

LCMS: m/z 360 [M+H]⁺

HPLC retention time: 2.83 min (analysis condition U)

Example 77 Compound A9-102-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-methyl-acetamide

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-aceticacid (Compound A8-7, 30 mg, 0.0838 mmol), methylamine hydrochloric acidsalt (28.1 mg, 0.417 mmol), EDC (32 mg, 0.167 mmol) and HOBT (0.023 mg,0.167 mmol) were dissolved in DMF (1 mL), and added withdiisopropylethylamine (0.145 mL, 0.833 mmol) at room temperature. Afterstirring at room temperature for 18 hr, water was added and theextraction was carried out with ethyl acetate. After washing withsaturated brine, the organic layer was dried over magnesium sulfate. Thedrying agent was removed by filtration and the residues obtained afterconcentration under reduced pressure were dissolved in dichloromethane,added with diethyl ether, and the precipitated title compound wasobtained (white solid, 19.7 mg, 63%).

¹H-NMR (300 MHz, DMSO) σ ppm 12.73 (s, 1H), 8.33 (d, 1H, J=8.1 Hz), 8.17(d, 1H, J=8.7 Hz), 8.13 (s, 1H), 8.00 (s, 1H), 7.62 (d, 1H, J=8.1 Hz),7.39 (d, 1H, J=2.4 Hz), 7.11 (dd, 1H, J=8.7 Hz, 2.4 Hz), 4.64 (s, 2H),3.17 (d, 1H, J=5.4 Hz), 2.69 (d, 1H, J=4.5 Hz), 1.76 (s, 6H)

LCMS: m/z 374 [M+H]⁺

HPLC retention time: 2.43 min (analysis condition U)

Example 78 Compound A9-112-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-acetamide

Under the same conditions as the method for synthesizing Compound A9-10,the title compound was prepared from Compound A8-7 andC-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine.

LCMS: m/z 474 [M+H]⁺

HPLC retention time: 2.20 min (analysis condition U)

Example 79 Compound A9-122-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2,3-dihydroxy-propyl)-acetamide

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound A9-11.

LCMS: m/z 434 [M+H]⁺

HPLC retention time: 1.72 min (analysis condition U)

Example 80 Compound A9-13 2-Methyl-acrylic acid2-[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetylamino]-ethylester

Under the same conditions as the method for synthesizing Compound A9-10,the title compound was prepared from Compound A8-7 and 2-methyl-acrylicacid 2-amino-ethyl ester.

LCMS: m/z 472 [M+H]⁺

HPLC retention time: 3.30 min (analysis condition U)

Example 81 Compound A9-142-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2-hydroxy-ethyl)-acetamide

2-Methyl-acrylic acid2-[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetylamino]-ethylester (Compound A9-13, 40 mg, 0.085 mmol) was dissolved in a mixturesolvent of methanol (2 mL) and water (2 mL), added with potassiumhydroxide (48 mg, 0.85 mmol), and then stirred at room temperature for18 hr. After the neutralization with 1 N hydrochloric acid, the reactionsolution was concentrated under reduced pressure. The resulting residueswere purified by amino silica gel to obtain the title compound (whitesolid, 8.9 mg, 26%).

¹H-NMR (300 MHz, DMSO) σ ppm 12.75 (s, 1H), 8.32 (d, 1H, J=8.1 Hz),8.17-8.13 (m, 2 Hz), 7.99 (s, 1H), 7.60 (d, 1H, J=8.1 Hz), 7.38 (d, 1H,J=1.8 Hz), 7.11 (dd, 1H, J=2.1 Hz, 8.7 Hz), 4.72 (t, 1H, J=5.7 Hz), 4.65(s, 1H), 3.48 (dd, 2H, J=12.0 Hz, 6.0 Hz), 3.26 (dd, 2H, J=12.0 Hz, 6.0Hz), 1.76 (s, 6H)

LCMS: m/z 404 [M+H]⁺

HPLC retention time: 2.83 min (analysis condition U)

Example 82 Compound A9-15-14-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetyl]-piperazine-1-carboxylicAcid Tert-Butyl Ester

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-aceticacid (Compound A8-7, 30 mg, 0.083 mmol), piperazine-1-carboxylic acidtert-butyl ester (31 mg, 2 eq.), and HOBt (30 mg, 3 eq.) were dissolvedin 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at roomtemperature overnight. Thereafter, the solvent was removed under reducedpressure and the resulting residues were purified by preparative TLC toobtain the title compound (20 mg).

LCMS: m/z 527, 471, 427[M−H]⁻

HPLC retention time: 2.77 min (analysis condition C)

Example 83 Compound A9-15-26,6-Dimethyl-11-oxo-8-(2-oxo-2-piperazin-1-yl-ethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrileHydrochloric Acid Salt

4-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetyl]-piperazine-1-carboxylicacid tert-butyl ester (Compound A9-15-1, 20 mg) was added with 4 Nhydrochloric acid and dioxane solution (1 ml), and stirred in an waterbath at 10° C. for 4 hr. Water was added to the reaction solution andthe resulting precipitates were filtered and dried to obtain the titlecompound (15 mg, white powder).

LCMS: m/z 429 [M+H]⁺

HPLC retention time: 0.81 min (analysis condition I)

Example 84 Compound A9-162-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2-cyano-ethyl)-acetamide

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-aceticacid (Compound A8-7, 30 mg, 0.083 mmol), 3-aminopropionitrile (12 mg, 2eq.) and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added withEDC (48 mg, 3 eq.), and stirred at room temperature overnight.Thereafter, the solvent was removed under reduced pressure and theresulting residues were purified by preparative TLC to obtain the titlecompound (23 mg).

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 2.27 min (analysis condition C)

Example 85 Compound A9-172-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2-cyano-ethyl)-N-methyl-acetamide

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-aceticacid (Compound A8-7, 30 mg, 0.083 mmol), N-methyl-3-aminopropionitrile(14 mg, 2 eq.) and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF,added with EDC (48 mg, 3 eq.), and stirred at room temperatureovernight. Thereafter, the solvent was removed under reduced pressureand the resulting residues were purified by preparative TLC to obtainthe title compound (7 mg).

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 2.33 min (analysis condition C)

Example 86 Compound A108-(Tert-butyl-dimethyl-silanyloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The DMF solution of8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A6, 100 mg, 0.331 mmol), imidazole (67.5 mg, 3 eq.) andtert-butylchlorodimethylsilane (92.4 mg, 1.5 eq.) was stirred overnightat room temperature. To the reaction solution, saturated aqueoussolution of sodium hydrogen carbonate was added followed by extractionwith tert-butylmethyl ether. The organic layer was washed with brine anddried over sodium sulfate. The drying agent was removed by filtrationand the residues obtained after concentration under reduced pressurewere purified by silica gel column chromatography (ethyl acetate/hexane)to obtain the target compound (white solid, 170 mg, 100%).

LCMS: m/z 417 [M+H]⁺

HPLC retention time: 3.38 min (analysis condition S)

Example 87 Compound A10-18-Methoxy-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the THF solution of triphenylphosphine (260 mg, 3 eq.),azodicarboxylic acid diisopropyl ester (0.195 ml, 3 eq.) was added andthe mixture was stirred at room temperature for 1 hr. Thereafter,8-(tert-butyldimethylsilanyloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A10, 138 mg, 0.331 mmol) and methanol (1 ml) were added andstirred overnight. The reaction solution was purified by HPLC to obtainthe target compound (44.8 mg, 41%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.44 (1H, d, J=8.1 Hz), 8.33 (1H, s), 8.14(1H, d, J=8.7 Hz), 7.66 (1H, dd, J=8.2, 1.1 Hz), 7.39 (1H, d, J=2.3 Hz),7.09 (1H, dd, J=8.7, 2.3 Hz), 4.17 (3H, s), 3.92 (3H, s), 1.88 (6H, s).

LCMS: m/z 331 [M+H]⁺

HPLC retention time: 2.35 min (analysis condition S)

Example 88 Compound A10-28-(1-Methanesulfonyl-piperidin-4-yloxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-4,the title compound was prepared from Compound A9-4.

LCMS: m/z 478 [M+H]⁺

HPLC retention time: 2.68 min (analysis condition U)

Example 89 Compound B1 Trifluoro-methanesulfonic Acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A6, 550 mg, 0.189 mmol) was dissolved in pyridine (18 mL),added with anhydrous trifluoromethanesulfonic acid (0.758 ml, 3 eq.),and stirred at room temperature for 30 min. The reaction solution wasadded to water and then extracted with dichloromethane. The organiclayer was dried over magnesium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/hexane) to obtain the target compound (white powder, 641 mg,81%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.89 (1H, br. s), 8.36 (1H, d, J=8.8 Hz),8.31 (1H, dd, J=8.1, 0.7 Hz), 8.11 (1H, d, J=2.3 Hz), 8.04 (1H, dd,J=1.5, 0.7 Hz), 7.65-7.60 (2H, m). 1.76 (6H, s)

LCMS: m/z 435 [M+H]⁺

HPLC retention time: 3.10 min (analysis condition U)

Example 90 Compound B2-18-(4-Isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Trifluoro-methanesulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester(Compound B1, 40 mg, 0.0921 mmol) was dissolved in NMP (1 ml) and addedwith 1-isopropylpiperazine (236 mg, 20 eq.). The mixture was stirred at120° C. for 3 hr. After cooling to room temperature, purification wascarried out by HPLC to obtain the target compound (white powder, 12.8mg, 34%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.30 (1H, d, 8.1 Hz), 8.03 (1H, d, 8.6 Hz),7.98 (1H, s), 7.56 (1H, d, 8.6 Hz), 7.21 (1H, s), 7.04 (1H, d, 9.1 Hz),3.40-3.37 (4H, m), 2.73-2.65 (1H, m), 2.61-2.58 (4H, m), 1.75 (6H, s),1.02 (6H, d, 6.6 Hz)

LCMS: m/z 413 [M+H]⁺

Example 91 Compound B2-28-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundB2-1, the title compound was prepared from Compound B1 andN-(2-hydroxyethyl)piperazine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.30 (1H, d, 8.1 Hz), 8.03 (1H, d, 8.7 Hz),7.99 (1H, s), 7.58 (1H, d, 7.9 Hz), 7.21 (1H, s), 7.04 (1H, d, 8.7 Hz),4.50-4.46 (1H, br m), 3.59-3.53 (2H, m), 3.39-3.35 (4H, m), 2.59-2.56(4H, m), 2.45 (2H, t, 6.1 Hz), 1.76 (6H, s)

LCMS: m/z 415 [M+H]⁺

HPLC retention time: 1.27 min (analysis condition S)

Example 92 Compound B2-36,6-Dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 and morpholine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.62 (1H, br. s), 8.29 (1H, d, 8.2 Hz),8.04 (1H, d, 9.0 Hz), 7.96 (1H, s), 7.56 (1H, d, 8.2 Hz), 7.22 (1H, s),7.04 (1H, d, 9.0 Hz), 3.77-3.75 (4H, m), 3.35-3.30 (4H, m), 1.74 (6H, s)

LCMS: m/z 372 [M+H]⁺

HPLC retention time: 2.45 min (analysis condition U)

Example 93 Compound B2-46,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 and4-pyrrolidin-1-yl-piperidine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.30 (1H, d, 8.1 Hz), 8.01 (1H, d, 8.7 Hz),7.97 (1H, s), 7.56 (1H, d, 8.6 Hz), 7.20 (1H, s), 3.94-3.90 (2H, m),3.30-3.28 (4H, m), 2.95 (2H, t, 11.8 Hz), 2.24-2.20 (1H, m), 1.95-1.91(2H, m), 1.75 (6H, s), 1.70-1.66 (4H, m), 1.54-1.52 (2H, m)

LCMS: m/z 439 [M+H]⁺

Example 94 Compound B2-5-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 andpiperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 471 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition S)

Example 95 Compound B2-5-26,6-Dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B2-5-1.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.32 (1H, d, 8.5 Hz), 8.03 (1H, d, 9.1 Hz),7.99 (1H, s), 7.59 (1H, dd, 8.2, 1.5 Hz), 7.20 (1H, d, 2.4 Hz), 7.04(1H, dd, 8.8, 2.1 Hz), 3.32-3.30 (4H, m), 2.88-2.87 (4H, m), 1.77 (6H,s)

LCMS: m/z 371 [M+H]⁺

Example 96 Compound B2-66,6-Dimethyl-11-oxo-8-piperidin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 and piperidine.

LCMS: m/z 370 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition U)

Example 97 Compound B2-7-18-(4-Hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 and piperidin-4-ol.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.30 (1H, d, 8.1 Hz), 8.01 (1H, d, 8.7 Hz),7.97 (1H, s), 7.56 (1H, d, 7.7 Hz), 7.19 (1H, s), 7.04 (1H, d, 10.6 Hz),4.76-4.71 (1H, br m), 3.81-3.75 (3H, m), 3.08 (2H, t, 10.2 Hz),1.86-1.82 (2H, m), 1.75 (6H, s), 1.49-1.42 (2H, m)

LCMS: m/z 386 [M+H]⁺

Example 98 Compound B2-7-26,6-Dimethyl-11-oxo-8-(4-oxo-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-(4-Hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound B2-7-1, 210 mg, 0.545 mmol), was dissolved in the DCM (2 mL)and DMF (0.6 mL) mixture solvent, added with1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (300 mg, 1.3eq.), and the mixture was stirred at room temperature for 2 hr. To thereaction solution, 0.25 mol/L aqueous solution of sodium thiosulfate,saturated sodium bicarbonate solution and CPME were added followed byfurther stirring at room temperature for 1 hr. The reaction solution wasfiltered and the filtrate was subjected to liquid separation. Theorganic layer was washed with saturated brine and dried over sodiumsulfate. The drying agent was removed by filtration and the residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetarget compound (yellowish white powder, 109 mg, 52%).

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 2.17 min (analysis condition U)

Example 99 Compound B2-88-(4-Methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 and1-methanesulfonylpiperazine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.66 (1H, br. s), 8.31 (1H, d, J=8.2 Hz),8.06 (1H, d, J=8.7 Hz), 7.99 (1H, s), 7.59 (1H, d, J=8.2 Hz), 7.30 (1H,d, J=1.8 Hz), 7.09 (1H, dd, J=8.7, 1.8 Hz), 3.53 (4H, t, J=4.8 Hz), 3.27(4H, t, J=4.8 Hz), 2.94 (3H, s), 1.77 (6H, s).

LCMS: m/z 449 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition S)

Example 100 Compound B2-98-(3-Methanesulfonyl-pyrrolidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 and3-methanesulfonylpyrrolidine.

LCMS: m/z 434 [M+H]⁺

HPLC retention time: 1.83 min (analysis condition S)

Example 101 Compound B2-108-(1,1-Dioxothiomorpholino)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Trifluoro-methanesulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester(Compound B1, 30 mg, 0.069 mmol) was dissolved in 1,4-dioxane (1 mL),added with thiomorpholine 1,1-dioxide (19 mg, 2 eq.), Pd₂ (dba)₃ (6.3mg, 0.1 eq.), BINAP (8.6 mg, 0.2 eq.) and K₃PO₄ (29 mg, 2 eq.), andstirred at 100° C. overnight. The reaction solution was added to water,and then extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over sodium sulfate. The drying agent wasremoved by filtration and the residues obtained after concentrationunder reduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the target compound (white powder, 2.1mg, 7%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.29 (1H, d, J=8.6 Hz), 8.07 (1H, d, J=8.9Hz), 8.00 (1H, s), 7.55 (1H, dd, J=8.5, 1.7 Hz), 7.34 (1H, d, J=2.0 Hz),7.15 (1H, dd, J=9.1, 2.7 Hz), 4.01 (4H, s), 3.16 (4H, s), 1.77 (6H, s).

LCMS: m/z 420 [M+H]⁺

HPLC retention time: 1.80 min (analysis condition S)

Example 102 Compound B2-118-(4-Cyclopentyl-2-oxo-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10,the title compound was prepared from Compound B1 and4-cyclopentylpiperazin-2-one.

LCMS: m/z 453 [M+H]⁺

HPLC retention time: 1.30 min (analysis condition S)

Example 103 Compound B2-126,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 and 4-piperidin-4-ylmorpholine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.73 (1H, s), 8.27-8.31 (1H, m), 7.98-8.02(1H, m), 7.95-7.97 (1H, m), 7.53-7.58 (1H, m), 7.17-7.21 (1H, m),6.99-7.05 (1H, m), 3.97-4.05 (2H, m), 3.53-3.59 (4H, m), 2.80-2.90 (2H,m), 2.43-2.51 (4H, m), 2.31-2.40 (1H, m), 1.83-1.92 (2H, m), 1.74 (6H,s), 1.39-1.52 (2H, m)

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 1.73 min (analysis condition U)

Example 104 Compound B2-138-(4,4-Difluoro-1,4′-bipiperidin-1′-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-7-2 and4,4-difluoropiperidine hydrochloric acid salt.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.59 (1H, s), 8.25-8.32 (1H, m), 7.97-8.02(1H, m), 7.96 (1H, s), 7.52-7.59 (1H, m), 7.16-7.21 (1H, m), 6.99-7.05(1H, mz), 4.00-4.09 (2H, m), 3.55-3.62 (2H, m), 2.79-2.90 (2H, m),2.55-2.67 (4H, m), 1.78-1.98 (5H, m), 1.74 (6H, s), 1.44-1.58 (2H, m)

LCMS: m/z 489 [M+H]⁺

HPLC retention time: 1.88 min (analysis condition U)

Example 105 Compound B2-148-[4-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-piperidin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-7-2 and(2R,6S)-2,6-dimethylmorpholine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.60 (1H, s), 8.25-8.31 (1H, m), 7.97-8.02(1H, m), 7.95 (1H, s), 7.51-7.58 (1H, m), 7.18 (1H, s), 6.99-7.05 (1H,m), 3.96-4. 06 (2H, m), 3.45-3.55 (2H, m), 2.80-2.91 (2H, m), 2.72-2.79(2H, m), 2.29-2.41 (1H, m), 1.70-1.90 (10H, m), 1.40-1.53 (2H, m), 1.03(6H, d, 6.3 Hz)

LCMS: m/z 483 [M+H]⁺

HPLC retention time: 1.83 min (analysis condition U)

Example 106 Compound B2-158-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound B1 and2,6-dimethylpiperazine.

LCMS: m/z 399 [M+H]⁺

HPLC retention time: 1.76 min (analysis condition U)

Example 107 Compound B2-16-1(S)-4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3-methyl-piperazine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound B2-10,the title compound was prepared from Compound B1 and(S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 485 [M+H]⁺

HPLC retention time: 3.97 min (analysis condition W)

Example 108 Compound B2-16-26,6-Dimethyl-8-((S)-2-methyl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound 2-16-1.

LCMS: m/z 385 [M+H]⁺

HPLC retention time: 2.43 min (analysis condition W)

Example 109 Compound B2-16-38-((S)-4-Cyclobutyl-2-methyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-16-2 and cyclobutanone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.31 (1H, d, 8 Hz), 8.03 (1H, d, 12 Hz),7.98 (1H, s), 7.59 (1H, d, 12 Hz), 7.13 (1H, s), 6.98 (1H, d, 8 Hz),4.35-4.28 (1H, m), 3.70 (1H, d, 12 Hz), 3.02 (1H, ddd, 12, 12, 4 Hz),2.87 (1H, d, 8 Hz), 2.74-2.67 (2H, m), 2.08-1.99 (2H, m), 1.92-1.64(10H, m), 1.70-1.62 (2H, m), 1.12 (3H, d, 8 Hz)

LCMS: m/z 439 [M+H]⁺

HPLC retention time: 2.59 min (analysis condition W)

Example 110 Compound B2-178-(2-Diethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Trifluoro-methanesulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester(Compound B1, 25 mg, 0.057 mmol) was dissolved in dimethoxyethane (0.5mL), added with 2-diethylaminoethanethiol hydrochloric acid salt (19.6mg, 2 eq.), Pd₂(dba)₃(2.6 mg, 0.05 eq.), Xantphos (3.3 mg, 0.1 eq.) andDIPEA (0.06 mg, 6 eq.), and the mixture was stirred at 160° C. for 30min. The reaction solution was added to water, extracted with ethylacetate, and dried over magnesium sulfate. The drying agent was removedby filtration and the residues obtained after concentration underreduced pressure were purified by silica gel column chromatography(dichloromethane/methanol) to obtain the target compound (whiteamorphous, 22.4 mg, 93%).

¹H-NMR (400 MHz, CDCl₃) δ: 9.60 (1H, s), 8.53-8.48 (1H, m), 8.32 (1H, d,J=8.4 Hz), 7.77 (1H, s), 7.53-7.50 (2H, m), 7.38-7.35 (1H, m), 3.18-3.12(2H, m), 2.81-2.75 (2H, m), 2.65-2.57 (4H, m), 1.76 (6H, s), 1.08-1.04(6H, m)

LCMS: m/z 418 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition U)

Example 111 Compound B2-188-(2-Diisopropylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17,the title compound was prepared from Compound B1 and2-diisopropylaminoethanethiol hydrochloric acid salt.

LCMS: m/z 446 [M+H]⁺

HPLC retention time: 2.22 min (analysis condition U)

Example 112 Compound B2-198-(2-Dimethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17,the title compound was prepared from Compound B1 and2-dimethylaminoethanethiol hydrochloric acid salt.

LCMS: m/z 390 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition U)

Example 113 Compound B2-203-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylsulfanyl)-propionic Acid

Under the same conditions as the method for synthesizing Compound B2-17,the title compound was prepared from Compound B1 and 3-mercaptopropionicacid.

LCMS: m/z 391 [M+H]⁺

HPLC retention time: 2.45 min (analysis condition U)

Example 114 Compound B2-218-(2,3-Dihydroxy-propylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17,the title compound was prepared from Compound B1 and3-mercaptopropane-1,2-diol.

LCMS: m/z 393 [M+H]⁺

HPLC retention time: 2.15 min (analysis condition U)

Example 115 Compound B2-22-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-Butyl Ester

To trifluoro-methanesulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester(Compound B1, 7.80 g, 18.0 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester (6.11 g, 19.8 mmol, 1.1 eq.), Pd(PPh₃)₂Cl₂ (630 mg, 0.898 mmol,0.05 eq.), and sodium carbonate (5.71 g, 53.9 mmol, 3.0 eq.), DME (125ml) and water (25 ml) were added. The mixture was subjected to reducedpressure under ultrasonication treatment, followed by flushing withnitrogen gas. This procedure was repeated five times and then degassed.After further stirring at 80° C. for 2 hr under nitrogen atmosphere, themixture was cooled to room temperature, added with water (250 ml), andfurther stirred for 30 min. The precipitates were filtered and washedwith water (50 ml). They were further washed with CH₃CN (50 ml) toobtain the target compound as a crude product (gray powder, 7.54 g,90%).

LCMS: m/z 468 [M+H]⁺

HPLC retention time: 2.90 min (analysis condition S)

Example 116 Compound B2-22-26,6-Dimethyl-11-oxo-8-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B2-22-1.

LCMS: m/z 368 [M+H]⁺

HPLC retention time: 1.47 min (analysis condition S)

Example 117 Compound B2-236,6-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB2-22-1, the title compound was prepared from Compound B1 and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

LCMS: m/z 367 [M+H]⁺

HPLC retention time: 2.42 min (analysis condition U)

Example 118 Compound B2-246,6-Dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere, trifluoro-methanesulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester(Compound B1, 1.00 g, 2.302 mmol) was added with n-propanol (20 mL),potassium vinyltrifluoroborate (854 mg, 3.0 eq.),dichloro-((bis-diphenylphosphino)ferrocenyl)palladium (217 mg, 0.1 eq.)and triethylamine (1.11 ml, 3.0 eq.) in order and the resultant wasstirred at 60° C. for 4 hr. Upon the completion of the reaction, waterwas added to the reaction solution. The resulting precipitates werefiltered and washed with distilled water, and the residues were dried toobtain the title compound (666 mg, 80%).

¹H-NMR (400 MHz, CDCl₃) δ: 8.90 (1H, s), 8.55 (1H, d, J=7.9 Hz), 8.40(1H, d, J=8.5 Hz), 7.79 (1H, s), 7.58-7.61 (3H, m), 6.85 (1H, dd,J=17.7, 11.0 Hz), 5.95 (1H, d, J=17.1 Hz), 5.46 (1H, d, J=11.0 Hz), 1.84(6H, s)

LCMS: m/z 313 [M+H]⁺

HPLC retention time: 3.75 min (analysis condition W)

Example 119 Compound B2-25-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylmethyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

4-Methylene-piperidine-1-carboxylic acid tert-butyl ester (409 mg, 2.07mmol, 1.2 eq.) was dissolved in THF (2 ml), added under nitrogenatmosphere with 9-BBN (0.5 M THF solution, 4.83 ml, 2.42 mmol, 1.4 eq.)and then stirred at 60° C. for 1 hr. Thereafter, 9-BBN (0.5 M THFsolution, 5.52 ml, 2.77 mmol, 1.6 eq.) was further added and the mixturewas stirred at 60° C. for 1 hr. The resulting mixture was cooled to roomtemperature, added with cesium fluoride (1.31 g, 8.60 mmol, 5.0 eq.),and stirred at room temperature for 30 min.

To the solution obtained from the above, DMF (18 ml) suspensioncomprising trifluoro-methanesulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester(Compound B1, 750 mg, 1.73 mmol) anddichloro-((bisdiphenylphosphino)ferrocenyl)palladium (70.5 mg, 0.0863mmol, 0.05 eq.) was added, and the mixture was stirred at 100° C. for 3hr. After cooling to the room temperature, water (50 ml) was added,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine and dried over sodium sulfate. The drying agent wasremoved by filtration and the residues obtained after concentrationunder reduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (yellow powder,763 mg, 91%).

LCMS: m/z 484 [M+H]⁺

HPLC retention time: 2.97 min (analysis condition S)

Example 120 Compound B2-25-2 6,6-Dimethyl-11-oxo-8-piperidin-4-ylmethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B2-25-1.

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 1.40 min (analysis condition S)

Example 121 Compound B2-26-1 Tert-butyl4-((3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)methyl)piperidin-1-ylsulfonylcarbamic Acid

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B2-25-2 andN-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (CAS No. 872496-91-8).

LCMS: m/z 563 [M+H]⁺

HPLC retention time: 2.63 min (analysis condition S)

Example 122 Compound B2-26-24-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylmethyl)-piperidine-1-sulfonic Acid Amide

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B2-26-1.

LCMS: m/z 463 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition S)

Example 123 Compound B2-27 8-(1-Isopropyl-piperidin-4-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-25-2 and acetone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.80 (1H, s), 8.32 (1H, d, 7.9 Hz), 8.12(1H, d, 7.9 Hz), 8.01 (1H, s), 7.65 (1H, s), 7.61 (1H, d, 9.1 Hz), 7.30(1H, d, 7.9 Hz), 2.75 (2H, d, 11.0 Hz), 2.65 (3H, q, 6.5 Hz), 2.04 (2H,t, 11.0 Hz), 1.77 (6H, s), 1.60-1.57 (3H, m), 1.22 (2H, t, 11.6 Hz),0.94 (6H, d, 6.7 Hz)

LCMS: m/z 426 [M+H]⁺

Example 124 Compound B2-283-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicAcid

Under nitrogen atmosphere, to the dimethyl formamide (3 ml) solutioncomprising trifluoro-methanesulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester(Compound B1, 150 mg, 0.345 mmol), lithium formate monohydrate (90 mg,5.0 eq.), 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene (Xantphos)(20 mg, 0.1 eq.), Pd₂(dba)₃ (32 mg, 0.1 eq.), lithium chloride (88 mg,6.0 eq.), N,N-diisopropylethylamine (241 μl, 4.0 eq.), and aceticanhydride (131 μl, 4.0 eq.) were added, and the mixture was stirred at80° C. for 15 hr. Upon the completion of the reaction, ethyl acetate wasadded to the reaction solution. The organic layer was washed in orderwith 1 M hydrochloric acid, distilled water, and brine. The organiclayer was dried over sodium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (88 mg, 76%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 13.17 (1H, s), 8.35 (1H, d, J=7.9 Hz), 8.34(1H, s), 8.23 (1H, d, J=7.9 Hz), 8.07 (1H, s), 8.02 (1H, d, J=9.1 Hz),7.64 (1H, d, J=7.9 Hz), 1.80 (6H, s)

LCMS: m/z 331 [M+H]⁺

HPLC retention time: 3.08 min (analysis condition W)

Example 125 Compound B2-298-Formyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the THF (24 ml) and distilled water (6 ml) suspension of6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound B2-24, 600 mg, 1.920 mmol), t-butanol solution of osmiumtetraoxide (192 μl, 0.1 eq.) and sodium meta periodate (821 mg, 2.0 eq.)were added and the mixture was stirred at room temperature for 3 hr.Aqueous solution of sodium thiosulfate (0.3 M) was added to thesolution, which was then extracted with an ethyl acetate. The organiclayer was washed with 10% aqueous solution of disodium ethylenediaminetetraacetic acid. The organic layer was dried over sodium sulfate. Thedrying agent was removed by filtration and the residues obtained afterconcentration under reduced pressure were purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (470mg, 77%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.95 (1H, s), 10.20 (1H, s), 8.48 (1H, s),8.42 (1H, d, J=8.5 Hz), 8.36 (1H, d, J=8.5 Hz), 8.07 (1H, s), 8.02 (1H,d, J=7.9 Hz), 7.67 (1H, d, J=7.9 Hz), 1.85 (6H, s)

LCMS: m/z 315 [M+H]⁺

HPLC retention time: 3.38 min (analysis condition W)

Example 126 Compound B3-15,6,6-Trimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A10-1,the title compound was prepared from Compound B2-3.

LCMS: m/z 386 [M+H]⁺

HPLC retention time: 2.62 min (analysis condition U)

Example 127 Compound B3-2-1 Tert-butyl4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-ylsulfonylcarbamic Acid

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B2-5-2 andN-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (CAS No. 872496-91-8).

LCMS: m/z 550 [M+H]⁺

HPLC retention time: 2.39 min (analysis condition S)

Example 128 Compound B3-2-24-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-sulfonicAcid Amide

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B3-2-1.

LCMS: m/z 450 [M+H]⁺

HPLC retention time: 1.82 min (analysis condition S)

Example 129 Compound B3-34-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B2-5-2 anddimethylsulfamoyl chloride.

LCMS: m/z 478 [M+H]⁺

HPLC retention time: 2.45 min (analysis condition S)

Example 130 Compound B3-44-(3-Cyano-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-sulfonicAcid Dimethylamide

To the DMF suspension of4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-sulfonicacid amide (Compound B3-2-2, 20 mg, 0.04 mmol) and sodium hydride (21.4mg, 12 eq.), iodomethane (28 μl, 10 eq.) was added and stirred at roomtemperature overnight. Water was added to the reaction solution,followed by filtration to obtain the target compound (25.8 mg, 100%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.43 (1H, d, J=8.2 Hz), 8.31 (1H, s), 8.03(1H, d, J=8.9 Hz), 7.64 (1H, dd, J=8.1, 1.3 Hz), 7.30 (1H, d, J=2.0 Hz),7.08 (1H, dd, J=8.9, 2.0 Hz), 4.16 (3H, s), 3.43-3.53 (4H, t, J=4.7 Hz),3.26-3.41 (4H, s), 2.82 (6H, s), 1.87 (6H, s).

LCMS: m/z 492 [M+H]⁺

HPLC retention time: 2.69 min (analysis condition S)

Example 131 Compound B3-58-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound F5-36.

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 1.31 min (analysis condition S)

Example 132 Compound B3-68-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-5-2 and cyclobutanone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.29 (1H, d, J=8.2 Hz), 8.01 (1H, d, J=8.8Hz), 7.96 (1H, s), 7.55 (1H, d, J=8.2 Hz), 7.19 (1H, d, J=2.2 Hz), 7.03(1H, dd, J=2.4, 8.8 Hz), 2.71-2.75 (1H, m), 2.37-2.39 (4H, m), 1.98-2.00(2H, m), 1.77-1.85 (2H, m), 1.74 (6H, s), 1.63-1.68 (2H, m).

LCMS: m/z 425 [M+H]⁺

HPLC retention time: 1.80 min (analysis condition U)

Example 133 Compound B3-76,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-5-2 and 3-oxetanone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.29 (1H, dd, J=8.2, 0.59 Hz), 8.02 (1H, d,J=9.0 Hz), 7.97 (1H, d, J=0.59 Hz), 7.56 (1H, dd, J=8.0, 1.4 Hz), 7.22(1H, d, J=2.3 Hz), 7.04 (1H, dd, J=8.8, 2.2 Hz), 4.56-4.59 (2H, m),4.47-4.50 (2H, m), 3.43-3.48 (1H, m), 3.39-3.42 (4H, m), 2.40-2.42 (4H,m), 1.74 (6H, s)

LCMS: m/z 427 [M+H]⁺

HPLC retention time: 1.67 min (analysis condition U)

Example 134 Compound B3-88-(2-Diethylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-(2-Diethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound B2-17, 16.8 mg, 0.0402 mmol) was dissolved in methanol (1.5mL), added with oxone (54.3 mg, 2.2 eq.) which had been dissolved inwater (0.5 mL), and then stirred at room temperature for 2 hr. Thereaction solution was concentrated, extracted with ethyl acetate, washedwith saturated sodium hydrogen carbonate, and dried over magnesiumsulfate. The drying agent was removed by filtration and the residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (dichloromethane/methanol) to obtainthe target compound (white solid, 5.8 mg, 32%).

¹H-NMR (400 MHz, CDCl₃) δ: 9.29 (1H, s), 8.61 (1H, d, J=8.2 Hz), 8.52(1H, d, J=8.0 Hz), 8.21 (1H, s), 8.01 (1H, d, J=8.2 Hz), 7.81 (1H, s),7.61 (1H, d, J=8.2 Hz), 3.33 (2H, t, J=7.4 Hz), 2.95 (2H, t, J=7.4 Hz),2.41 (4H, q, J=7.2 Hz), 1.86 (6H, s), 0.89 (4H, t, J=7.1 Hz)

LCMS: m/z 450 [M+H]⁺

HPLC retention time: 2.05 min (analysis condition U)

Example 135 Compound B3-98-(2-Diisopropylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8,the title compound was prepared from Compound B2-18.

LCMS: m/z 478 [M+H]⁺

HPLC retention time: 2.18 min (analysis condition U)

Example 136 Compound B3-108-(2-Dimethylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8,the title compound was prepared from Compound B2-19.

LCMS: m/z 422 [M+H]⁺

HPLC retention time: 2.03 min (analysis condition U)

Example 137 Compound B3-113-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-sulfonyl)-propionicAcid

Under the same conditions as the method for synthesizing Compound B3-8,the title compound was prepared from Compound B2-20.

LCMS: m/z 423 [M+H]⁺

HPLC retention time: 2.28 min (analysis condition U)

Example 138 Compound B3-128-(2,3-Dihydroxy-propane-1-sulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8,the title compound was prepared from Compound B2-21.

LCMS: m/z 425 [M+H]⁺

HPLC retention time: 2.17 min (analysis condition U)

Example 139 Compound B3-13-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-carboxylicacid tert-butyl ester

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (Compound B2-22-1, 16.2 g, 34.6 mmol) wasdissolved in THF (800 ml) and methanol (230 ml), added with 10 wt % Pd/C(3.2 g), and stirred under hydrogen atmosphere for 19 hr. The solid wasfiltered through Celite, eluted with a mixture solvent (400 ml;THF/methanol=4/1), and concentrated under reduced pressure. The residueswere dissolved in ethyl acetate (400 ml), and then washed with 1%aqueous solution of N-acetylcysteine, saturated aqueous solution ofNaHCO₃ and saturated brine. The organic layer was dried over sodiumsulfate. The drying agent was removed by filtration and the residueswere concentrated under reduced pressure to obtain the title compound asa crude product (white powder, 14.0 g, 86%).

LCMS: m/z 470 [M+H]⁺

HPLC retention time: 2.88 min (analysis condition S)

Example 140 Compound B3-13-26,6-Dimethyl-11-oxo-8-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B3-13-1.

LCMS: m/z 370 [M+H]⁺

HPLC retention time: 1.30 min (analysis condition S)

Example 141 Compound B3-148-(1,2-Dihydroxy-ethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the THF (1 ml) solution of6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound B2-24, 20 mg, 0.064 mmol), t-butanol solution of osmiumtetraoxide (19 μl, 0.3 eq.) and 50% aqueous solution ofN-methylmorpholine-N-oxide (30 μl, 2.0 eq.) were added and the mixturewas stirred at room temperature for 3 hr. To the reaction solution, 10%aqueous solution of disodium ethylenediamine tetraacetic acid was added,followed by extraction with ethyl acetate. The organic layer was driedover sodium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure werepurified by high performance liquid chromatography to obtain the titlecompound (21 mg, 63%).

¹H-NMR (400 MHz, CD₃OD) δ: 8.41 (1H, d, J=7.9 Hz), 8.29 (1H, d, J=7.9Hz), 7.87 (1H, s), 7.86 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.52 (1H, d,J=6.7 Hz), 4.85 (1H, dd, J=7.0, 4.6 Hz), 3.73 (1H, dd, J=11.3, 4.6 Hz),3.68 (1H, dd, J=11.3, 7.0 Hz), 1.83 (6H, s)

LCMS: m/z 347 [M+H]⁺

HPLC retention time: 2.68 min (analysis condition W)

Example 142 Compound B3-156,6-Dimethyl-8-(morpholine-4-carbonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the tetrahydrofuran (1 ml) solution of3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid (Compound B2-28, 15 mg, 0.045 mmol), morpholine (6 μl, 1.5 eq.),hexafluorophosphoric acid uronium2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylmethane aminium (HATU)(26 mg, 1.5 eq.), and N,N-diisopropylethylamine (24 μl, 3.0 eq.) wereadded and the mixture was stirred at room temperature for 3 hr. Thereaction solution was filtered to remove insoluble matters and theresidues obtained after concentration under reduced pressure werepurified by high performance liquid chromatography to obtain the titlecompound (11 mg, 55%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.85 (1H, s), 8.33 (1H, d, J=8.5 Hz), 8.27(1H, d, J=7.9 Hz), 8.03 (1H, s), 7.92 (1H, s), 7.63 (1H, d, J=8.5 Hz),7.54 (1H, d, J=7.9 Hz), 3.52-3.77 (6H, m), 3.30-3.42 (2H, m), 1.79 (6H,s)

LCMS: m/z 400 [M+H]⁺

HPLC retention time: 2.96 min (analysis condition W)

Example 143 Compound B3-168-(4-Methanesulfonyl-piperazin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and1-methanesulfonylpiperazine.

LCMS: m/z 477 [M+H]⁺

HPLC retention time: 3.03 min (analysis condition W)

Example 144 Compound B3-178-(4-Hydroxy-piperidin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and piperidin-4-ol.

LCMS: m/z 414 [M+H]⁺

HPLC retention time: 2.75 min (analysis condition W)

Example 145 Compound B3-183-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid (2-hydroxy-1-hydroxymethyl-ethyl)-amide

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and2-aminopropane-1,3-diol.

LCMS: m/z 404 [M+H]⁺

HPLC retention time: 2.60 min (analysis condition W)

Example 146 Compound B3-193-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid (2-methanesulfonyl-ethyl)-amide

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and2-methanesulfonylethylamine.

LCMS: m/z 436 [M+H]⁺

HPLC retention time: 2.87 min (analysis condition W)

Example 147 Compound B3-203-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid (1,1-dioxo-tetrahydro-thiophen-3-yl)-amide

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and(1,1-dioxotetrahydrothiophen-3-yl)amine

LCMS: m/z 448 [M+H]⁺

HPLC retention time: 1.70 min (analysis condition S)

Example 148 Compound B3-213-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid ((R)-2,3-dihydroxy-propyl)-amide

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and(R)-(+)-3-amino-1,2-propanediol.

LCMS: m/z 404 [M+H]⁺

HPLC retention time: 1.38 min (analysis condition S)

Example 149 Compound B3-223-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid bis-(2-hydroxy-ethyl)-amide

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 andN,N-diethanolamine.

LCMS: m/z 418 [M+H]⁺

HPLC retention time: 1.35 min (analysis condition S)

Example 150 Compound B3-233-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid oxetan-3-yl amide

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and oxetan-3-ylamine.

LCMS: m/z 386 [M+H]⁺

HPLC retention time: 1.63 min (analysis condition S)

Example 151 Compound B3-243-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid (2-hydroxy-ethoxy)-amide

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and2-aminooxy-ethanol.

LCMS: m/z 390 [M+H]⁺

HPLC retention time: 1.54 min (analysis condition S)

Example 152 Compound B3-25-12-[(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carbonyl)-amino]-ethyl}-carbamicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and(2-amino-ethyl)-carbamic acid tert-butyl ester.

LCMS: m/z 473 [M+H]⁺

HPLC retention time: 2.08 min (analysis condition S)

Example 153 Compound B3-25-23-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid (2-amino-ethyl)-amide

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B3-25-1.

LCMS: m/z 373 [M+H]⁺

HPLC retention time: 1.19 min (analysis condition S)

Example 154 Compound B3-25-33-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicAcid (2-Methanesulfonylamino-Ethyl)-Amide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B3-25-2.

LCMS: m/z 451 [M+H]⁺

HPLC retention time: 1.62 min (analysis condition S)

Example 155 Compound B3-263-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylicacid (2-hydroxy-ethyl)-methyl-amide

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and2-methylamino-ethanol.

LCMS: m/z 388 [M+H]⁺

HPLC retention time: 1.53 min (analysis condition S)

Example 156 Compound B3-27-1 Tert-butylN-(2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8carboxamide)ethyl)sulfamoylcarbamicAcid

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B3-25-2 andN-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (CAS No. 872496-91-8).

LCMS: m/z 552 [M+H]⁺

HPLC retention time: 2.03 min (analysis condition S)

Example 157 Compound B3-27-23-Cyano-6,6-dimethyl-11-oxo-N-(2-(sulfamoylamino)ethyl)-6,11-dihydro-5H-benzo[b]carbazol-8-carboxamide

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B3-27-1.

LCMS: m/z 452 [M+H]⁺

HPLC retention time: 1.57 min (analysis condition S)

Example 158 Compound B3-288-[4-(2-Hydroxy-ethyl)-piperazin-1-carbonyl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and 2-piperazin-1-ylethanol.

LCMS: m/z 443 [M+H]⁺

HPLC retention time: 1.75 min (analysis condition U)

Example 159 Compound B3-298-(4-Tert-butyl-piperazin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and1-tert-butylpiperazine.

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 1.88 min (analysis condition U)

Example 160 Compound B3-308-[4-(2-Methoxy-ethyl)-piperazin-1-carbonyl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 and1-(2-methoxyethyl)piperazine.

LCMS: m/z 457 [M+H]⁺

HPLC retention time: 1.83 min (analysis condition U)

Example 161 Compound B3-31-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carbonyl)-piperazine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound B2-28 andpiperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 499 [M+H]⁺

HPLC retention time: 2.63 min (analysis condition U)

Example 162 Compound B3-31-26,6-Dimethyl-11-oxo-8-(piperazin-1-carbonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B3-31-1.

LCMS: m/z 399 [M+H]⁺

HPLC retention time: 1.78 min (analysis condition U)

Example 163 Compound B3-32 6,6-Dimethyl-8-morpholin-4-ylmethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the THF (1 ml) solution of Compound B2-29 (30 mg, 0.095 mmol),morpholine (6 μl, 1.5 eq.) and sodium triacetoxyborohydride (81 mg, 2.0eq.) were added and stirred at room temperature for 1 hr. The reactionsolution was filtered to remove insoluble matters, and the residuesobtained after concentration under reduced pressure were purified byhigh performance liquid chromatography to obtain the title compound (19mg, 50%).

¹H-NMR (400 MHz, CD₃OD) δ: 8.41 (1H, d, 7.9 Hz), 8.27 (1H, d, 8.5 Hz),7.87 (1 s), 7.81 (1H, s), 7.56 (1H, d, 8.5 Hz), 7.49 (1H, d, 7.9 Hz),3.71 (4H, t, 4.6 Hz), 3.68 (2H, s), 2.51 (4H, t, 4.6 Hz), 1.82 (6H, s)

LCMS: m/z 386 [M+H]⁺

HPLC retention time: 2.41 min (analysis condition W)

Example 164 Compound B3-33 6,6-Dimethyl-8-(4-methyl-piperazin-1-ylmethyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-29 and1-methylpiperazine.

¹H-NMR (400 MHz, CD₃OD) δ: 8.41 (1H, d, 7.9 Hz), 8.26 (1H, d, 7.9 Hz),7.88 (1 s), 7.81 (1H, s), 7.56 (1H, d, 7.9 Hz), 7.48 (1H, d, 7.9 Hz),3.70 (2H, s), 2.42-2.78 (8H, m), 2.31 (3H, s), 1.82 (6H, s)

LCMS: m/z 399 [M+H]⁺

HPLC retention time: 2.30 min (analysis condition W)

Example 165 Compound B3-348-[4-(1,1-Dioxide-4-thiomorpholinyl)methyl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-29 and thiomorpholine1,1-dioxide.

LCMS: m/z 434 [M+H]⁺

HPLC retention time: 2.75 min (analysis condition W)

Example 166 Compound B3-35 8-(4-Methanesulfonyl-piperazin-1-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-29 and1-methanesulfonylpiperazine.

¹H-NMR (400 MHz, CD₃OD) δ: 8.41 (1H, d, 8.5 Hz), 8.28 (1H, d, 7.9 Hz),7.87 (1 s), 7.80 (1H, s), 7.56 (1H, d, 8.5 Hz), 7.50 (1H, d, 7.9 Hz),3.73 (2H, s), 3.24-3.28 (4H, m), 2.85 (3H, s), 2.59-2.65 (4H, m), 1.82(6H, s)

LCMS: m/z 463 [M+H]⁺

HPLC retention time: 2.47 min (analysis condition W)

Example 167 Compound B3-364-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylmethyl)-piperazine-1-sulfonic Acid Dimethylamide

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-29 andpiperazine-1-sulfonic acid dimethylamide.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.79 (1H, s), 8.32 (1H, d, 7.9 Hz), 8.18(1H, d, 7.9 Hz), 8.00 (1 s), 7.77 (1H, s), 7.60 (1H, d, 7.9 Hz), 7.46(1H, d, 7.9 Hz), 3.67 (2H, s), 3.18-3.23 (4H, m), 2.76 (6H, s),2.45-2.50 (4H, m), 1.77 (6H, s)

LCMS: m/z 492 [M+H]⁺

HPLC retention time: 2.58 min (analysis condition W)

Example 168 Compound B3-376,6-Dimethyl-11-oxo-8-[(2,2,2-trifluoro-ethylamino)-methyl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B2-29 and2,2,2-trifluoroethylamine.

LCMS: m/z 398 [M+H]⁺

HPLC retention time: 2.73 min (analysis condition W)

Example 169 Compound B3-388-Hydroxymethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The by-product obtained from the synthesis of Compound B3-37 waspurified by high performance liquid chromatography to obtain the targetcompound.

LCMS: m/z 317 [M+H]⁺

HPLC retention time: 2.91 min (analysis condition W)

Example 170 Compound B4-18-(1-Cyclobutyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B3-13-2 and cyclobutanone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.73 (1H, s), 8.28-8.33 (1H, m), 8.09-8.14(1H, m), 7.99 (1H, s), 7.72 (1H, s), 7.56-7.62 (1H, m), 7.34-7.41 (1H,m), 3.52-3.64 (2H, m), 2.85-2.95 (2H, m), 2.56-2.75 (2H, m), 1.91-2.04(2H, m), 1.56-1.84 (14H, m)

LCMS: m/z 424 [M+H]⁺

HPLC retention time: 1.87 min (analysis condition U)

Example 171 Compound B4-28-(1-Methanesulfonyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B3-13-2 and mesylchloride.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.77 (1H, s), 8.31 (1H, d, 8.6 Hz), 8.15(1H, d, 8.2 Hz), 8.00 (1H, s), 7.77 (1H, s), 7.59 (1H, d, 7.3 Hz), 7.42(1H, d, 8.6 Hz), 3.74-3.70 (1H, m), 2.93 (3H, s), 2.86-2.77 (4H, m),1.93-1.87 (4H, m), 1.77 (6.0H, s)

LCMS: m/z 448 [M+H]⁺

HPLC retention time: 2.37 min (analysis condition S)

Example 172 Compound B4-3-1Tert-butyl4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-1-ylsulfonylcarbamic Acid

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B3-13-2 andN-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridine-1-yl-sulfonyl]azanide.

LCMS: m/z 549 [M+H]⁺

HPLC retention time: 2.72 min (analysis condition S)

Example 173 Compound B4-3-24-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-sulfonicAcid Amide

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B4-3-1.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.78 (1H, s), 8.29 (1H, d, 7.9 Hz), 8.14(1H, d, 8.5 Hz), 7.97 (1H, s), 7.76 (1H, s), 7.55 (1H, d, 8.5 Hz), 7.41(1H, d, 7.9 Hz), 6.79 (2H, s), 3.63 (2H, d, 12.2 Hz), 2.80-2.73 (1H, m),2.70-2.64 (2H, m), 1.96-1.93 (2H, m), 1.87-1.81 (2H, m), 1.77 (6H, s)

LCMS: m/z 449 [M+H]⁺

HPLC retention time: 2.03 min (analysis condition S)

Example 174 Compound B4-44-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-sulfonicAcid Methylamide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B3-13-2 and2-oxooxazolidine-3-sulfonic acid methylamide.

LCMS: m/z 463 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition S)

Example 175 Compound B4-54-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-sulfonicacid dimethylamide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B3-13-2 anddimethylsulfamoyl chloride.

LCMS: m/z 477 [M+H]⁺

HPLC retention time: 2.65 min (analysis condition S)

Example 176 Compound B4-66,6-Dimethyl-8-(1-methyl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B3-13-2 and iodomethane.

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 1.50 min (analysis condition S)

Example 177 Compound B4-78-(1-Isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B3-13-2 and acetone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.77 (1H, s), 8.32 (1H, d, 7.9 Hz), 8.13(1H, d, 7.9 Hz), 8.01 (1H, s), 7.73 (1H, s), 7.61 (1H, d, 9.1 Hz), 7.39(1H, d, 9.8 Hz), 2.93 (2H, d, 11.0 Hz), 2.77-2.71 (1H, m), 2.67-2.62(1H, m), 2.25 (2H, t, 10.1 Hz), 1.80-1.73 (10H, m), 1.02 (6H, d, 6.7 Hz)

LCMS: m/z 412 [M+H]⁺

HPLC retention time: 1.60 min (analysis condition S)

Example 178 Compound B4-86,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound B3-13-2 and oxetan-3-one.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.74 (1H, s), 8.32 (1H, d, 7.9 Hz), 8.13(1H, d, 7.9 Hz), 8.00 (1H, s), 7.74 (1H, s), 7.61 (1H, d, 9.8 Hz), 7.40(1H, d, 7.9 Hz), 4.56 (2H, t, 6.7 Hz), 4.46 (2H, t, 6.1 Hz), 3.46-3.39(1H, m), 2.85-2.82 (2H, m), 2.71-2.64 (1H, m), 1.92-1.86 (2H, m),1.82-1.79 (4H, m), 1.77 (6H, s)

LCMS: m/z 426 [M+H]⁺

HPLC retention time: 1.53 min (analysis condition S)

Sulfuric acid salt of Compound B4-8

6,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilewas dissolved at 80° C. in a mixture of 5 volumes of DMA and 1.4 volumesof 2 N sulfuric acid. After cooling to room temperature, 15 volumes ofacetone were added dropwise, and the precipitated solids were filteredand dried to obtain sulfuric acid salt of6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.81 (1H, s), 10.26 (1H, br. s), 8.33 (1H,d, 8.3 Hz), 8.21 (1H, d, 8.3 Hz), 8.04 (1H, s), 7.75 (1H, s), 7.63 (1H,d, 8.3 Hz), 7.41 (1H, d, 8.3 Hz), 4.85-4.70 (4H, m), 4.50-4.40 (1H, br.s), 3.60-3.00 (6H, br. m), 2.20-2.10 (2H, m), 2.05-1.90 (2H, m), 1.79(6H, s)

LCMS: m/z 426 [M+H]⁺

Example 179 Compound B4-94-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-carboxylicAcid Ethylamide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound B-3-13-2 andethylisocyanate.

LCMS: m/z 441 [M+H]⁺

HPLC retention time: 2.20 min (analysis condition S)

Example 180 Compound B4-108-[1-(Imidazole-1-sulfonyl)-piperidin-4-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the method disclosed in Journal of Organic Chemistry, 2003,page 115,6,6-dimethyl-11-oxo-8-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound B3-13-2, 10 mg, 0.027 mmol) was reacted with3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium (19 mg, 2 eq.).After removing the solvent, the residues were purified by liquidchromatography to obtain the title compound (3 mg).

LCMS: m/z 500 [M+H]⁺

HPLC retention time: 2.80 min (analysis condition C)

Example 181 Compound CC13-Methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-sulfonylchloride

To the dichloromethane (2 ml) solution of7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 200mg, 0.980 mmol), chlorosulfonic acid (110 μl, 1.70 eq.) was added andthe mixture was stirred at room temperature for 2 hr. To the reactionsolution, oxalyl chloride (297 μl, 3.0 eq.) and N,N-dimethyl formamide(45 μl, 0.6 eq.) were added in three divided portions, and the mixturewas stirred at room temperature for 30 min. The reaction solution wasconcentrated under reduced pressure to obtain the title compound (295mg). Since the title compound is unstable, its structure was identifiedin the next step.

Example 182 Compound CC2-17-Methoxy-1,1-dimethyl-6-(pyrrolidine-1-sulfonyl)-3,4-dihydro-1H-naphthalen-2-one

The THF (4 ml) solution of3-methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-sulfonylchloride (Compound CC1, 295 mg, 0.974 mmol) was cooled to 0° C., and thetetrafuran (1 ml) solution combining pyrrolidine (121 μl, 1.5 eq.) andtriethylamine (272 μl, 2 eq.) was added dropwise thereto over 2 min. Themixture was stirred at 0° C. until Compound CC-1 disappears. Thereaction solution was added with distilled water and extracted withethyl acetate. The organic layer was washed with 10% aqueous solution ofdisodium ethylenediamine tetraacetic acid. The organic layer was washedwith brine and dried over sodium sulfate. The drying agent was removedby filtration and the residues obtained after concentration underreduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (246 mg, 75%).

¹H-NMR (400 MHz, CDCl₃) δ: 7.76 (1H, s), 6.93 (1H, s), 3.95 (3H, s),3.37-3.46 (4H, m), 3.09 (0.0H, t, J=6.9 Hz), 2.69 (0.0H, t, J=6.9 Hz),1.82-1.91 (4H, m), 1.47 (6H, s)

LCMS: m/z 338 [M+H]⁺

HPLC retention time: 3.21 min (analysis condition W)

Example 183 Compound CC2-27-Methoxy-1,1-dimethyl-6-(4-methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-naphthalen-2-one

Under the same conditions as the method for synthesizing Compound CC2-1,the title compound was prepared from Compound CC1 andN-methylpiperazine.

LCMS: m/z 367 [M+H]⁺

HPLC retention time: 2.22 min (analysis condition Y)

Example 184 Compound CC3-18-Methoxy-6,6-dimethyl-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E2-1,the title compound was prepared from Compound CC2-1.

LCMS: m/z 436 [M+H]⁺

HPLC retention time: 3.76 min (analysis condition W)

Example 185 Compound CC3-23-Bromo-8-methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A3-1,the title compound was prepared from Compound CC2-2.

LCMS: m/z 519 [M+H]⁺

HPLC retention time: 2.99 min (analysis condition Y)

Example 186 Compound CC4-18-Methoxy-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound CC3-1.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.86 (1H, s), 8.60 (1H, s), 8.30 (1H, d,J=8.5 Hz), 8.01 (1H, s), 7.60 (1H, s), 7.59 (1H, d, J=8.5 Hz), 4.09 (3H,s), 3.21-3.42 (4H, m), 1.72-1.90 (10H, m)

LCMS: m/z 450 [M+H]⁺

HPLC retention time: 3.40 min (analysis condition W)

Example 187 Compound CC4-23-Bromo-8-methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound CC3-2.

LCMS: m/z 532, 534 [M+H]⁺

HPLC retention time: 2.18 min (analysis condition U)

Example 188

Compound CC-4-3

8-Methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A5-2,the title compound was prepared from Compound CC4-2.

LCMS: m/z 479 [M+H]⁺

HPLC retention time: 1.93 min (analysis condition U)

Example 189 Compound C1-1 Dimethyl-sulfamic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound A6, 50 mg, 0.165 mmol) was dissolved in DMF (1.5 mL), addedwith sodium hydride (13 mg, 2.0 eq.) and dimethylsulfamoyl chloride(0.02 mL, 1.2 eq.), and then stirred at room temperature for 1 hr. Waterwas added to the reaction solution, which was then extracted with ethylacetate. The organic layer was washed with saturated brine and driedover sodium sulfate. The drying agent was removed by filtration and theresidues were concentrated under reduced pressure to obtain the targetcompound (yellowish white powder, 62 mg, 92%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.87 (1H, s), 8.40-8.30 (2H, m), 8.05 (1H,s), 7.82 (1H, d, J=1.8 Hz), 7.64 (1H, d, J=7.9 Hz), 7.50 (1H, dd, J=8.5,2.4 Hz), 2.96 (6H, s), 1.81 (6H, s)

LCMS: m/z 410 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition S)

Example 190 Compound C1-2 Morpholine-4-sulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl Ester

According to the same method as the method for synthesizing CompoundA8-17, the title compound was prepared as a crude product from CompoundA6 and Compound A8-18-0.

Example 191 Compound C1-4 4-Methyl-piperazine-1-sulfonic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl Ester

According to the same method as the method for synthesizing CompoundA8-17, the title compound was prepared as a crude product from CompoundA6 and Compound A8-19-0.

Example 192 Compound C2-13-Cyano-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

To dimethyl-sulfamic acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester(Compound C1-1, 250 mg, 0.610 mmol), aluminum chloride (1.0 M,nitromethane solution (1.8 mL, 3.0 eq.)) was added and the mixture wasstirred at 160° C. for 10 min under irradiation with microwave. Waterwas added to the reaction solution, which was then extracted withdichloromethane. The organic layer was washed with saturated brine anddried over sodium sulfate. The drying agent was removed by filtrationand the residues obtained after concentration under reduced pressurewere purified by silica gel column chromatography(dichloromethane/methanol) to obtain the target compound (yellowishwhite powder, 99 mg, 40%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.78 (1H, s), 11.72 (1H, s), 8.50 (1H, s),8.32 (1H, d, J=8.5 Hz), 8.02 (1H, s), 7.62 (1H, d, J=7.9 Hz), 7.25 (1H,s), 2.80 (6H, s), 1.75 (6H, s).

LCMS: m/z 410 [M+H]⁺

HPLC retention time: 2.00 min (analysis condition S)

Example 193 Compound C2-28-Hydroxy-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound CC4-1.

LCMS: m/z 436 [M+H]⁺

HPLC retention time: 3.32 min (analysis condition W)

Example 194 Compound C2-38-Hydroxy-6,6-dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound C2-1,the title compound was prepared from Compound C1-2.

LCMS: m/z 452 [M+H]⁺

HPLC retention time: 1.89 min (analysis condition S)

Example 195 Compound C2-48-Hydroxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound CC4-3.

LCMS: m/z 465 [M+H]⁺

HPLC retention time: 1.87 min (analysis condition U)

Example 196 Compound C3-1 Trifluoro-methanesulfonic Acid3-cyano-9-dimethylsulfamoyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylEster

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound C2-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 13.05 (1H, s), 8.67 (1H, s), 8.32 (1H, d,J=8.2 Hz), 8.06 (2H, m), 7.67 (1H, dd, J=7.9, 1.3 Hz), 2.79 (6H, s),1.84 (6H, s).

LCMS: m/z 542 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition S)

Example 197 Compound C3-2 Trifluoro-methanesulfonic Acid3-cyano-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazol-8-ylEster

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound C2-2.

LCMS: m/z 568 [M+H]⁺

HPLC retention time: 4.00 min (analysis condition W)

Example 198 Compound C4-13-Cyano-8-(2-methoxy-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound C2-1 and1-bromo-2-methoxy-ethane.

¹H-NMR (300 MHz, DMSO-d₆) σppm; 12.8 (s, 1H), 8.58 (s, 1H), 8.31 (d, 1H,J=8.4 Hz), 8.03 (s, 1H), 7.62 (m, 2H), 4.47 (m, 2H), 3.75 (m, 2H), 3.32(s, 3H), 2.27 (s, 6H), 1.83 (s, 6H)

LCMS: m/z 468 [M+H]⁺

HPLC retention time: 2.68 min (analysis condition U)

Example 199 Compound C4-23-Cyano-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound C2-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.57 (1H, s), 8.29 (1H, d, J=8.4 Hz), 8.02(1H, s), 7.70-7.60 (2H, m), 4.37 (2H, t, J=6.3 Hz), 2.84 (2H, m), 2.80(6H, s), 2.64-2.53 (4H, m), 1.83 (6H, s), 0.98 (6H, t, J=7.1 Hz).

LCMS: m/z 509 [M+H]⁺

HPLC retention time: 1.55 min (analysis condition S)

Example 200 Compound C4-33-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound C2-1 and iodomethane.

LCMS: m/z 424 [M+H]⁺

HPLC retention time: 2.17 min (analysis condition S)

Example 201 Compound C4-4 3-Cyano-6,6-dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A7-1and Compound A8-1, the title compound was prepared from Compound C2-1and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 493 [M+H]⁺

HPLC retention time: 1.49 min (analysis condition S)

Example 202 Compound C4-53-Cyano-6,6-dimethyl-8-(2-morpholin-4-yl-ethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound C2-1 and2-morpholin-4-yl-ethanol.

LCMS: m/z 523 [M+H]⁺

HPLC retention time: 1.64 min (analysis condition S)

Example 203 Compound C4-63-Cyano-8-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound C2-1 and2-(1,1-dioxothiomorpholino)ethanol.

LCMS: m/z 571 [M+H]⁺

HPLC retention time: 1.75 min (analysis condition S)

Example 204 Compound C4-7 3-Cyano-8-(1-ethyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound C2-1 and1-ethyl-piperidin-4-ol.

LCMS: m/z 521 [M+H]⁺

HPLC retention time: 1.52 min (analysis condition S)

Example 205 Compound C4-83-Cyano-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound C3-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.61 (1H, s), 8.30 (1H, d, J=8.1 Hz), 8. 04(1H, s), 7.87 (1H, s), 7.62 (1H, dd, J=8.2, 1.8 Hz), 3.17-3.06 (2H, m),2.75-2.70 (6H, s), 2.67-2.58 (2H, m), 1.81 (6H, s), 1.02 (6H, d, J=6.4Hz).

LCMS: m/z 520 [M+H]⁺

HPLC retention time: 1.52 min (analysis condition S)

Example 206 Compound C4-93-Cyano-8-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound C3-1 and2-piperazin-1-yl-ethanol.

LCMS: m/z 522 [M+H]⁺

HPLC retention time: 1.40 min (analysis condition S)

Example 207 Compound C4-103-Cyano-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound C3-1 and morpholine.

LCMS: m/z 479 [M+H]⁺

HPLC retention time: 2.22 min (analysis condition S)

Example 208 Compound C4-114-(3-Cyano-9-dimethylsulfamoyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound C3-1 andpiperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 578 [M+H]⁺

HPLC retention time: 2.72 min (analysis condition S)

Example 209 Compound C4-123-Cyano-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from C₄₋₁₁.

¹H-NMR (270 MHz, CD₃OD) δ: 8.78 (1H, s), 8.39 (1H, dd, J=8.2, 0.7 Hz),7.88 (1H, m), 7.75 (1.1H, s), 7.55 (1H, dd, J=8.2, 1.5 Hz), 3.15 (4H,m), 3.04 (4H, m), 2.82 (s, 6H), 1.85 (6H, s)

LCMS: m/z 478 [M+H]⁺

HPLC retention time: 1.43 min (analysis condition S)

Example 210 Compound C4-136,6-Dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound C3-2 and4-(1-pyrrolidyl)-piperidine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.83 (1H, s), 8.64 (1H, s), 8.32 (1H, d,8.2 Hz), 8.03 (1H, s), 7.80 (1H, s), 7.63 (1H, d, 8.2 Hz), 2.87-2.94(4H, m), 1.94-1.99 (4H, m), 1.80 (6H, s), 1.58-1.76 (10H, m)

LCMS: m/z 572 [M+H]⁺

HPLC retention time: 2.81 min (analysis condition W)

Example 211 Compound C4-148-(2-Diethylamino-ethoxy)-6,6-dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound C2-3.

LCMS: m/z 551 [M+H]⁺

HPLC retention time: 1.46 min (analysis condition S)

Example 212 Compound C4-156,6-Dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound C2-3 andtetrahydropyran-4-ol.

LCMS: m/z 536 [M+H]⁺

HPLC retention time: 2.05 min (analysis condition S)

Example 213 Compound C4-166,6-Dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound C2-4 andtetrahydropyran-4-ol.

LCMS: m/z 549 [M+H]⁺

HPLC retention time: 2.03 min (analysis condition U)

Example 214 Compound C4-178-(2-Diethylamino-ethoxy)-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the target compound was prepared from Compound C2-3.

LCMS: m/z 564 [M+H]⁺

HPLC retention time: 1.20 min (analysis condition S)

Example 215 Compound C53-Cyano-8-methoxy-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

The title compound was obtained as a by-product of the synthesis ofCompound C4-3.

LCMS: m/z 438 [M+H]⁺

HPLC retention time: 2.29 min (analysis condition S)

Example 216 Compound D0-1-17-Methoxy-1,1-dimethyl-6-nitro-3,4-dihydro-1H-naphthalen-2-one

Tetrabutylammonium nitrate (2.47 g, 1.07 eq.) was dissolved indichloromethane, and added with trifluoromethanesulfonic anhydride (1.33ml, 1.07 eq.) at 0° C. The mixture was stirred for 1 hr, added with DCMsolution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(Compound A2, 1.55 g, 7.59 mmol), and then stirred at 0° C. for 2 hr and30 min. The reaction solution was added to saturated aqueous solution ofsodium hydrogen carbonate and then extracted with ethyl acetate. Theorganic layer was washed with brine and dried over sodium sulfate. Thedrying agent was removed by filtration and the residues obtained afterconcentration under reduced pressure were purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (paleyellow solid, 1.144 g, 60%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 7.79 (1H, s), 7.28 (1H, s), 3.95 (3H, s),3.06 (2H, t, J=6.9 Hz), 2.64 (2H, t, J=6.9 Hz), 1.41 (6H, s).

HPLC retention time: 2.03 min (analysis condition S)

Example 217 Compound D0-1-27-Methoxy-1,1-dimethyl-8-nitro-3,4-dihydro-1H-naphthalen-2-one

The title compound was obtained as a by-product of the synthesis ofCompound D0-1-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 7.44 (1H, d, J=8.6 Hz), 7.23 (1H, d, J=8.6Hz), 3.84 (3H, s), 3.07 (2H, t, J=6.9 Hz), 2.65 (2H, t, J=6.9 Hz), 1.35(6H, s)

HPLC retention time: 2.15 min (analysis condition S)

Example 218 Compound D0-2-13-Bromo-8-methoxy-6,6-dimethyl-9-nitro-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A3-1,the title compound was prepared from Compound D0-1-1.

LCMS: m/z 401,403 [M+H]⁺

HPLC retention time: 3.07 min (analysis condition S)

Example 219 Compound D0-2-23-Bromo-8-methoxy-6,6-dimethyl-7-nitro-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A3-1,the title compound was prepared from Compound D0-1-2.

LCMS: m/z 401, 403 [M+H]⁺

HPLC retention time: 3.10 min (analysis condition S)

Example 220 Compound D0-3-13-Bromo-8-methoxy-6,6-dimethyl-9-nitro-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound D0-2-1.

LCMS: m/z 415, 417 [M+H]⁺

HPLC retention time: 3.07 min (analysis condition S)

Example 221 Compound D0-3-23-Bromo-8-methoxy-6,6-dimethyl-7-nitro-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound D0-2-2.

LCMS: m/z 415, 417 [M+H]⁺

HPLC retention time: 2.72 min (analysis condition S)

Example 222 Compound D0-4-18-Methoxy-6,6-dimethyl-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A5-2,the title compound was prepared from Compound D0-3-1.

LCMS: m/z 362 [M+H]⁺

HPLC retention time: 2.35 min (analysis condition S)

Example 223 Compound D0-4-28-Methoxy-6,6-dimethyl-7-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A5-2,the title compound was prepared from Compound D0-3-2.

LCMS: m/z 362 [M+H]⁺

HPLC retention time: 2.35 min (analysis condition S)

Example 224 Compound D0-5-18-Hydroxy-6,6-dimethyl-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound D0-4-1.

LCMS: m/z 348 [M+H]⁺

HPLC retention time: 2.28 min (analysis condition S)

Example 225 Compound D0-5-28-Hydroxy-6,6-dimethyl-7-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound D0-4-2.

LCMS: m/z 348 [M+H]⁺

HPLC retention time: 2.23 min (analysis condition S)

Example 226 Compound D1 6,6-Dimethyl-8-(1-methyl-piperidin-4-yloxy)-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound D0-5-1 and1-methylpiperidin-4-ol.

LCMS: m/z 445 [M+H]⁺

HPLC retention time: 1.64 min (analysis condition S)

Example 227 Compound D2 9-Amino-6,6-dimethyl-8-(1-methyl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6,6-Dimethyl-8-(1-methyl-piperidin-4-yloxy)-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound D1, 83 mg, 0.19 mmol) was dissolved in ethanol, added withaqueous solution of ammonium acetate and aqueous solution of titanium(III) chloride, and then the mixture was stirred at room temperature for45 min. The reaction solution was added to saturated aqueous solution ofsodium hydrogen carbonate and then extracted with ethyl acetate. Theorganic layer was washed with brine and dried over sodium sulfate. Thedrying agent was removed by filtration and the residues wereconcentrated under reduced pressure to obtain the title compound (yellowsolid, 60 mg, 78%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.61 (1H, br. s), 8.28-8.34 (1H, m),7.94-8.00 (1H, m), 7.57 (1H, dd, J=8.2, 1.4 Hz), 7.46 (1H, s), 7.19 (1H,s), 4.93 (1.8H, s), 4.65 (1.0H, s), 4.06-4.15 (1H, m), 3.34 (5.7H, s),3.16-3.18 (2H, m), 2.55-2.67 (2H, m), 2.17-2.33 (5H, m), 1.89-2.07 (2H,m), 1.65-1.81 (8H, m)

LCMS: m/z 415 [M+H]⁺

HPLC retention time: 1.12 min (analysis condition S)

Example 228 Compound D3-1N-[3-Cyano-6,6-dimethyl-8-(1-methyl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound D2 and methanesulfonylchloride.

LCMS: m/z 493 [M+H]⁺

HPLC retention time: 1.43 min (analysis condition S)

Example 229 Compound D3-23-Cyano-6,6-dimethyl-11-oxo-8-(1-methylpiperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic Acid Dimethylamide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound D2 and dimethylsulfamoylchloride.

¹H-NMR (270 MHz, CD₃OD) δ: 8.34-8.42 (2. OH, m), 7.85 (1.0H, s),7.47-7.58 (1.0H, m), 7.32 (1.0H, s), 4.73-4.89 (1H, m), 2.75-2.91 (8H,m), 2.38-2.52 (2H, m), 2.34 (3H, s), 2.06-2.21 (2H, m), 1.87-2.05 (2H,m), 1.80 (6H, s).

LCMS: m/z 522 [M+H]⁺

HPLC retention time: 1.66 min (analysis condition S)

Example 230 Compound D3-3N-[3-Cyano-6,6-dimethyl-8-(1-methyl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl]-2-dimethylamino-acetamide

Under the same conditions as the method for synthesizing Compound A9-10,the title compound was prepared from Compound D2 andN,N-dimethylglycine.

LCMS: m/z 500 [M+H]⁺

HPLC retention time: 1.31 min (analysis condition S)

Example 231 Compound E16-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.0g, 9.791 mmol) was dissolved in CH₃CN (40 mL), added with NBS (1.92 g,1.1 eq.), and the mixture was stirred at room temperature for 2.5 hr.The reaction solution was added to water (40 mL), and the precipitatedsolid was filtered to obtain the title compound (white powder, 2.55 g,92%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.36 (1H, s), 6.84 (1H, s), 3.91 (3H, s),3.02 (2H, t, J=6.8 Hz), 2.66 (2H, t, J=6.8 Hz), 1.42 (6H, s).

LCMS: m/z 283, 285 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition S)

Example 232 Compound E2-19-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (CompoundE1, 7.89 g, 27.85 mmol) and 3-hydrazino-benzonitrile (4.45 g, 1.2 eq.)were dissolved in TFA (250 mL), and stirred at 100° C. for 2 hr. TFA wasremoved under reduced pressure and the residues were added withsaturated aqueous solution of NaHCO₃ (500 mL), followed by extractionwith ethyl acetate. The organic layer was washed with saturated brineand dried over sodium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were added with ethyl acetate. After stirring at roomtemperature, the precipitated solid was separated by filtration(Compound E2-2). The filtrate was concentrated under reduced pressure toobtain the title compound as a mixture with E2-2 (yellowish whitepowder, 2.65 g).

LCMS: m/z 381, 383 [M+H]⁺

HPLC retention time: 3.03 min (analysis condition S)

Example 233 Compound E2-29-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound E2-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 11.70 (1H, s), 7.69 (1H, dd, J=8.1, 0.8Hz), 7.55 (1H, s), 7.48 (1H, dd, J=7.4, 0.8 Hz), 7.27 (1H, s), 7.22 (1H,dd, J=8.1, 7.4 Hz), 4.23 (2H, s), 3.91 (3H, s), 1.70 (6H, s).

LCMS: m/z 381, 383 [M+H]⁺

HPLC retention time: 2.92 min (analysis condition S)

Example 234 Compound E2-3, Compound E2-43,9-Dibromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole1,9-Dibromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared (as a mixture) from Compound E1.

Example 235 Compound E3-1-19-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound E2-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.82 (1H, s), 8.30 (2H, s+d), 8.03 (1H,s), 7.61 (1H, dd, J=8.2, 1.4 Hz), 7.49 (1H, s), 4.04 (3H, s), 1.81 (6H,s).

LCMS: m/z 395, 397 [M+H]⁺

HPLC retention time: 2.77 min (analysis condition S)

Example 236 Compound E3-1-29-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound E3-1-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.84 (1H, s), 8.31 (1H, s), 7.86 (1H, dd,J=8.2, 0.9 Hz), 7.70 (1H, d, J=7.1 Hz), 7.47 (1H, s), 7.43 (1H, t, J=7.8Hz), 4.04 (3H, s), 1.81 (6H, s).

LCMS: m/z 395, 397 [M+H]⁺

HPLC retention time: 2.42 min (analysis condition S)

Example 237 Compound E3-1-33,9-Dibromo-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound E2-3 and Compound E2-4(mixture).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.42 (1H, s), 8.28 (1H, s), 8.09 (1H, d,J=8.2 Hz), 7.68 (1H, d, J=1.6 Hz), 7.47 (1H, s), 7.39 (1H, dd, J=8.3,1.7 Hz), 4.03 (3H, s), 1.78 (6H, s).

LCMS: m/z 448, 450, 452 [M+H]⁺

HPLC retention time: 2.93 min (analysis condition S)

Example 238 Compound E3-29-Bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound E3-1-1, 1.0 g, 2.53 mmol) was dissolved in NMP (10 mL), addedwith NaOMe (683 mg, 5 eq.) and 1-dodecanethiol (3.0 mL, 5 eq.), andstirred at 160° C. for 1 hr. The reaction solution was added to 0.5 Naqueous solution of hydrochloric acid, and then extracted with ethylacetate. The organic layer was washed with saturated brine and driedover sodium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure were addedwith MeOH, and the solid remaining after dissolution was filtered toobtain the title compound (yellow powder, 1.88 g, 65%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.77 (1H, s), 11.13 (1H, d, J=2.4 Hz),8.31 (1H, dd, J=7.9, 2.4 Hz), 8.25 (1H, d, J=3.0 Hz), 8.01 (1H, s), 7.61(1H, d, J=7.9 Hz), 7.28 (1H, d, J=2.4 Hz), 1.74 (6H, s).

LCMS: m/z 381, 383 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition S)

Example 239 Compound E3-39-Bromo-8-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound E3-2 and 2-bromopropane.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.77 (1H, s), 8.29 (2H, s+d), 8.01 (1H,s), 7.60 (1H, d, J=8.1 Hz), 7.50 (1H, s), 5.03 (1H, m), 1.79 (6H, s),1.36 (6H, d, J=5.9 Hz).

LCMS: m/z 423, 425 [M+H]⁺

HPLC retention time: 2.98 min (analysis condition S)

Example 240 Compound E4-18-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3,9-dicarbonitrile

Under the same conditions as the method for synthesizing Compound A5-2,the title compound was prepared from Compound E3-1-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.88 (1H, br. s), 8.43 (1H, s), 8.30 (1H,d, J=8.2 Hz), 8.05 (1H, d, J=0.5 Hz), 7.65-7.62 (2H, m), 4.11 (3H, s),1.84 (6H, s).

LCMS: m/z 342 [M+H]⁺

HPLC retention time: 2.23 min (analysis condition S)

Example 241 Compound E4-2-19-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound E3-1-1, 50 mg, 0.13 mmol), bis (acetonitrile)dichloropalladium(II) (1.64 mg, 0.05 eq.), XPhos (9.05 mg, 0.15 eq.), cesium carbonate(185 mg, 4.5 eq.) and 3-methyl-1-butyn-1-ol (18.6 μl, 1.5 eq.) weredissolved in acetonitrile and stirred at 85° C. for 2 hr. The reactionsolution was added to water, and then extracted with ethyl acetate. Theorganic layer was washed with brine and dried over sodium sulfate. Thedrying agent was removed by filtration and the residues obtained afterconcentration under reduced pressure were purified by HPLC to obtain thetitle compound (brown solid, 21.3 mg, 42%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.29 (1H, d, J=8.1 Hz), 8.11 (1H, s), 8.00(1H, s), 7.57 (1H, d, J=8.1 Hz), 7.40 (1H, s), 5.50 (1H, s), 3.95 (3H,s), 2.54 (1H, s), 1.79 (6H, s), 1.49 (6H, s).

LCMS: m/z 399 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition S)

Example 242 Compound E4-2-29-Ethynyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound E4-2-1, 21.3 mg, 0.05 mmol) and sodium hydride (3.2 mg, 1.5eq.) were dissolved in THF, and the mixture was stirred overnight at 50°C. Water was added to the reaction solution and the residues obtainedafter concentration under reduced pressure were purified by HPLC toobtain the title compound (brown solid, 9.6 mg, 31%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.26 (1H, d, J=8.2 Hz), 8.16 (1H, s), 7.97(1H, s), 7.53 (1H, d, J=8.2 Hz), 7.41 (1H, s), 4.32 (1H, s), 4.00 (3H,s), 1.79 (6H, s).

LCMS: m/z 341 [M+H]⁺

HPLC retention time: 2.27 min (analysis condition S)

Example 243 Compound E4-38-Methoxy-6,6-dimethyl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound E3-1-1, 50 mg, 0.13 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethanecomplex (1:1) (10.3 mg, 0.1 eq.), TEA (53 μl, 3 eq.) and potassiumvinyltrifluoroborate (51 mg, 3 eq.) were dissolved in n-propanol and themixture was stirred at 60° C. for 5 days. The reaction solution wasadded to water and then extracted with ethyl acetate. The organic layerwas washed with brine and dried over sodium sulfate. The drying agentwas removed by filtration and the residues obtained after concentrationunder reduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (brown powder, 25mg, 19%).

LCMS: m/z 343 [M+H]⁺

HPLC retention time: 2.55 min (analysis condition S)

Example 244 Compound E4-49-(2-Diethylamino-ethylsulfanyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17,the title compound was prepared from Compound E3-1-1.

LCMS: m/z 448 [M+H]⁺

HPLC retention time: 2.05 min (analysis condition U)

Example 245 Compound E4-59-Isopropylsulfanyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17,the title compound was prepared from Compound E3-1-1 and sodium salt ofpropane-2-thiol.

LCMS: m/z 391 [M+H]⁺

HPLC retention time: 2.98 min (analysis condition U)

Example 246 Compound E4-68-Methoxy-6,6-dimethyl-9-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10,the title compound was prepared from Compound E3-1-1 and1-methylpiperazine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.25 (1H, d, J=7.8 Hz), 7.93 (1H, s), 7.65(1H, s), 7.50 (1H, d, J=6.8 Hz), 7.25 (1H, s), 3.93 (3H, s), 3.02 (4H,br), 2.22 (3H, s), 1.73 (6H, s).

LCMS: m/z 415 [M+H]⁺

HPLC retention time: 1.80 min (analysis condition U)

Example 247 Compound E4-7-14-(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-Butyl Ester

To9-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound E3-1-1, 300 mg, 0.759 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (282 mg, 0.911 mmol, 1.2 eq.), Pd(PPh₃)₂Cl₂ (26.6mg, 0.0379 mmol, 0.05 eq.) and sodium carbonate (241 mg, 2.28 mmol, 3.0eq.), DME (5 ml) and water (1 ml) were added. The mixture was subjectedto reduced pressure under ultrasonication treatment, followed byflushing with nitrogen gas. This procedure was repeated five times andthen degassed. The mixture was stirred at 80° C. for 80 min undernitrogen atmosphere. Pd(PPh₃)₂Cl₂ (26.6 mg, 0.0379 mmol, 0.05 eq.) wasadded and the mixture was further stirred at 80° C. for 20 min. Then,the mixture was cooled to room temperature, and added with water andethyl acetate. The insoluble matters were filtered through Celite. Theorganic layer was dried over sodium sulfate. The drying agent wasremoved by filtration, followed by concentration under reduced pressureto obtain the title compound as a crude product (gray powder).

LCMS: m/z 498 [M+H]⁺

HPLC retention time: 2.85 min (analysis condition S)

Example 248 Compound E4-7-28-Methoxy-6,6-dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B4-4-1.

LCMS: m/z 368 [M+H]⁺

HPLC retention time: 1.27 min (analysis condition S)

Example 249 Compound E4-8-14-(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-piperidine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound B4-7-1.

LCMS: m/z 500 [M+H]⁺

HPLC retention time: 4.18 min (analysis condition W)

Example 250 Compound E4-8-28-Methoxy-6,6-dimethyl-11-oxo-9-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound B4-8-1.

LCMS: m/z 400 [M+H]⁺

HPLC retention time: 1.35 min (analysis condition S)

Example 251 Compound E4-9-14-(3-Cyano-8-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound E3-3.

LCMS: m/z 526 [M+H]⁺

HPLC retention time: 3.13 min (analysis condition S)

Example 252 Compound E4-9-28-Isopropoxy-6,6-dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound E4-9-1.

LCMS: m/z 426 [M+H]⁺

HPLC retention time: 1.40 min (analysis condition S)

Example 253 Compound E4-109-Cyclopropyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound E3-1-1 andpotassium cyclopropyltrifluoroborate.

LCMS: m/z 357 [M+H]⁺

HPLC retention time: 2.62 min (analysis condition S)

Example 254 Compound E4-113-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-carboxylicAcid

Under the same conditions as the method for synthesizing Compound B2-28,the title compound was prepared from Compound E3-1-1.

LCMS: m/z 361 [M+H]⁺

HPLC retention time: 1.68 min (analysis condition S)

Example 255 Compound E5-19-Ethyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The ethyl acetate suspension of8-methoxy-6,6-dimethyl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound E4-3, 25 mg, 0.07 mmol) and palladium carbon (25 mg) werestirred at room temperature for 1 hr under hydrogen atmosphere. Thereaction solution was filtered through Celite. The filtrate wasconcentrated under reduced pressure and the resulting residues werepurified by high performance liquid chromatography to obtain the titlecompound (white solid, 3.2 mg, 13%).

LCMS: m/z 345 [M+H]⁺

HPLC retention time: 2.62 min (analysis condition S)

Example 256 Compound E5-29-(2-Diethylamino-ethanesulfonyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8,the title compound was prepared from Compound E4-4.

LCMS: m/z 480 [M+H]⁺

HPLC retention time: 1.97 min (analysis condition U)

Example 257 Compound E5-38-Methoxy-6,6-dimethyl-11-oxo-9-(propane-2-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8,the title compound was prepared from Compound E4-5.

LCMS: m/z 423 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition U)

Example 258 Compound E5-49-(1-Isopropyl-piperidin-4-yl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound E4-8-2 and acetone.

LCMS: m/z 442 [M+H]⁺

HPLC retention time: 1.48 min (analysis condition S)

Example 259 Compound E5-58-Methoxy-6,6-dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound E4-7-2 and oxetan-3-one.

LCMS: m/z 454 [M+H]⁺

HPLC retention time: 1.32 min (analysis condition S)

Example 260 Compound E5-68-Isopropoxy-6,6-dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound E4-9-2 and oxetan-3-one.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.71 (1H, s), 8.31 (1H, d, J=8.2 Hz), 7.99(1H, s), 7.94 (1H, s), 7.58 (1H, d, J=7.6 Hz), 7.33 (1H, s), 5.84 (1.0H,m), 4.95 (1H, m), 4.56 (4H, dt, J=17.4, 6.3 Hz), 3.56 (1H, m), 3.01 (2H,br), 1.78 (6H, s), 1.34 (6H, d, J=5.9 Hz).

LCMS: m/z 482 [M+H]⁺

HPLC retention time: 1.43 min (analysis condition S)

Example 261 Compound E5-79-(4-Isopropyl-piperazin-1-carbonyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound E4-11 and1-isopropylpiperazine.

LCMS: m/z 471 [M+H]⁺

HPLC retention time: 1.18 min (analysis condition S)

Example 262 Compound E5-88-Methoxy-6,6-dimethyl-9-(morpholine-4-carbonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15,the title compound was prepared from Compound E4-11 and morpholine.

LCMS: m/z 430 [M+H]⁺

HPLC retention time: 1.68 min (analysis condition S)

Example 263 Compound E6-1(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-propionicAcid Methyl Ester

To the mixture of9-ethynyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound E4-2, 27 mg, 0.079 mmol), palladium (II) chloride (2.0 mg,0.14 eq.), copper (II) chloride (25.0 mg, 2.2 eq.), and sodium acetate(14.1 mg, 2.13 eq.), methanol (1.5 mL) was added, and then the mixturewas stirred at room temperature for 2 days under carbon monoxideatmosphere. The mixture was extracted with water and ethyl acetate andthe insoluble matters were filtered off. The organic layer was washedwith brine and dried over magnesium sulfate. The residues obtained afterfiltration and concentration under reduced pressure were washed withdichloromethane to obtain the title compound (13.9 mg, 44%).

LCMS: m/z 399 [M+H]⁺

HPLC retention time: 2.81 min (analysis condition F)

Example 264 Compound E6-2(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-propynoicAcid

(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-propynoicacid methyl ester (Compound E6-1, 15.2 mg, 0.038 mmol) was dissolved ina mixture solvent of methanol (1.5 mL) and THF (0.5 mL), added with 2 Naqueous solution of potassium hydroxide (5 drops), and then stirred atroom temperature overnight. 0.5 N Hydrochloric acid was added to thereaction solution, which was then extracted with ethyl acetate. Theorganic layer was washed with brine and dried over magnesium sulfate.The solids obtained after filtration and concentration under reducedpressure were washed with dichloromethane and purified by HPLC to obtainthe title compound (white solid, 9.6 mg, 66%).

LCMS: m/z 385 [M+H]⁺

HPLC retention time: 2.35 min (analysis condition F)

Example 265 Compound E6-39-(3-Hydroxy-3-methyl-butyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound E4-2-1, 21.0 mg, 0.0527 mmol) was dissolved in ethanol (15 mL)and N,N-dimethylacetamide (2 mL), added with 10% Pd/C (6.7 mg), and thenstirred at room temperature overnight under hydrogen atmosphere. Thereaction solution was filtered and concentrated under reduced pressure.The resulting residues were diluted with ethyl acetate, washed withbrine, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The resulting solid was washed with dichloromethane toobtain the title compound (yellow powder, 16.9 mg, 80%).

LCMS: m/z 403 [M+H]⁺

HPLC retention time: 5.39 min (analysis condition H)

Example 266 Compound F1-14-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound E3-2 and4-trifluoromethanesulfonyloxy-piperidine-1-carboxylic acid tert-butylester.

LCMS: m/z 564, 566 [M+H]⁺

HPLC retention time: 3.30 min (analysis condition S)

Example 267 Compound F1-2 9-Bromo-6,6-dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound F1-1.

LCMS: m/z 464, 466 [M+H]⁺

HPLC retention time: 1.52 min (analysis condition S)

Example 268 Compound F1-3 9-Bromo-8-(1-methanesulfonyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound F1-2 and methanesulfonylchloride.

LCMS: m/z 542, 544 [M+H]⁺

HPLC retention time: 2.57 min (analysis condition S)

Example 269 Compound F1-49-Bromo-6,6-dimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound E3-2 andtetrahydropyran-4-ol.

LCMS: m/z 465, 467 [M+H]⁺

HPLC retention time: 2.70 min (analysis condition S)

Example 270 Compound F2 Trifluoro-methanesulfonic Acid9-bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylester

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound E3-2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.99 (1H, s), 8.51 (1H, s), 8.31 (1H, dd,J=8.2, 0.7 Hz), 8.17 (1H, s), 8.07 (1H, s), 7.67 (1H, dd, J=8.2, 1.4Hz), 1.81 (6H, s).

LCMS: m/z 513, 515 [M+H]⁺

HPLC retention time: 3.13 min (analysis condition S)

Example 271 Compound F3-19-Bromo-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F1-2 and oxetan-3-one.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.29 (1H, d, 8 Hz), 8.29 (1H, s), 8.01 (1H,s), 7.60 (1H, d, 8 Hz), 7.55 (1H, s), 5.00-4.95 (1H, m), 4.55 (2H, dd,8, 8 Hz), 4.44 (2H, dd, 8, 8 Hz), 2.52-2.46 (1H, m), 2.33-2.29 (2H, m),1.96-1.94 (2H, m), 1.79 (8H, br. s)

LCMS: m/z 519, 521 [M+H]⁺

HPLC retention time: 2.78 min (analysis condition W)

Example 272 Compound F3-29-Bromo-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 and4-pyrrolidin-1-yl-piperidine.

LCMS: m/z 517, 519 [M+H]⁺

HPLC retention time: 1.70 min (analysis condition S)

Example 273 Compound F3-39-Bromo-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 and1-methanesulfonylpiperazine.

LCMS: m/z 527, 529 [M+H]⁺

HPLC retention time: 2.48 min (analysis condition S)

Example 274 Compound F3-49-Bromo-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 and morpholine.

LCMS: m/z 450, 452 [M+H]⁺

HPLC retention time: 2.65 min (analysis condition S)

Example 275 Compound F3-59-Bromo-8-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 and 2-piperazin-1-ylethanol.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.26 (2.0H, s+d), 7.97 (1H, s), 7.54 (1H,d, J=8.7 Hz), 7.43 (1H, s), 4.45 (1H, t, J=5.4 Hz), 3.55 (2H, q, J=5.8Hz), 3.17 (4H, br), 2.66 (2H, br), 1.76 (6H, s).

LCMS: m/z 493, 495 [M+H]⁺

HPLC retention time: 1.43 min (analysis condition S)

Example 276 Compound F3-6-1[1-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-carbamicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 andpiperidin-4-yl-carbamic acid tert-butyl ester.

LCMS: m/z 563, 565 [M+H]⁺

HPLC retention time: 3.05 min (analysis condition S)

Example 277 Compound F3-6-28-(4-Amino-piperidin-1-yl)-9-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound F3-6-1.

LCMS: m/z 463, 465 [M+H]⁺

HPLC retention time: 1.47 min (analysis condition S)

Example 278 Compound F3-79-Bromo-8-(4-hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 and piperidin-4-ol.

LCMS: m/z 464, 466 [M+H]⁺

HPLC retention time: 2.25 min (analysis condition S)

Example 279 Compound F3-89-Bromo-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 and1-isopropylpiperazine.

LCMS: m/z 491, 493 [M+H]⁺

HPLC retention time: 1.58 min (analysis condition S)

Example 280 Compound F3-99-Bromo-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 and piperazine.

¹H-NMR (DMSO-d₆) δ: 8.30-8.24 (2H, m), 8.00 (1H, s), 7.63-7.58 (1H, m),7.37 (1H, s), 3.10-3.01 (4H, m), 2.91-2.85 (4H, m), 1.76 (6H, s)

LCMS: m/z 449, 451 [M+H]⁺

HPLC retention time: 1.45 min (analysis condition S)

Example 281 Compound F3-104-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 andpiperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 549, 551 [M+H]⁺

HPLC retention time: 4.61 min (analysis condition W)

Example 282 Compound F3-119-Bromo-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound F2 and 4-piperidin-4-ylmorpholine.

¹H-NMR (DMSO-d₆) δ: 8.30-8.24 (2H, m), 8.00 (1H, s), 7.59 (1H, d, J=8.2Hz), 7.42 (1H, s), 3.66-3.45 (6H, m), 2.80 (2H, t, J=11.1 Hz), 2.38-2.28(1H, m), 1.96-1.87 (2H, m), 1.75 (6H, s), 1.66-1.56 (2H, m)

LCMS: m/z 533, 535 [M+H]⁺

HPLC retention time: 1.53 min (analysis condition S)

Example 283 Compound F4-1-19-Ethynyl-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound F3-1.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.30 (1H, d, 8 Hz), 8.17 (1H, s), 8.01 (1H,s), 7.60 (1H, d, 8 Hz), 7.50 (1H, s), 4.87-4.83 (1H, m), 4.55 (2H, dd,4, 4 Hz), 4.45 (2H, dd, 4, 4 Hz), 3.44 (1H, ddd, 4, 4, 4 Hz), 2.33-2.24(2H, m), 1.99-1.91 (2H, m), 1.78 (8H, br. s)

LCMS: m/z 466 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition W)

Example 284 Compound F4-1-29-Ethyl-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F4-1-1.

LCMS: m/z 470 [M+H]⁺

HPLC retention time: 2.74 min (analysis condition W)

Example 285 Compound F4-2N-[1-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound F3-6-2 and methanesulfonylchloride.

LCMS: m/z 541, 543 [M+H]⁺

HPLC retention time: 2.37 min (analysis condition S)

Example 286 Compound F4-39-Bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F3-9 and 1-oxetan-3-one.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.83 (1H, br. s), 8.31-8.32 (1H, m),8.27-8.29 (1H, m), 8.01-8.04 (1H, m), 7.59-7.64 (1H, m), 7.48 (1H, s),4.59 (2H, dd, J=6.3, 6.3 Hz), 4.48 (2H, dd, J=6.3, 6.3 Hz), 3.52 (1H, t,J=6.3 Hz), 3.12-3.25 (4H, m), 2.44-2.54 (4H, m), 1.78 (6H, s).

LCMS: m/z 505, 507 [M+H]⁺

HPLC retention time: 1.45 min (analysis condition S)

Hydrochloric Acid Salt of Compound F4-3

9-Bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilewas added with DMSO and 6 N hydrochloric acid (1.05 eq.) and dissolvedtherein. After freeze-drying, crystallization was performed by usingethanol comprising 25% water to obtain monohydrochloric acid salt of9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.91 (1H, br. s), 11.70 (1H, br. s),8.32-8.29 (2H, m), 8.04 (1H, s), 7.64-7.62 (1H, m), 7.52 (1H, s),4.89-4.62 (4H, br. m), 3.66-3.39 (1H, m), 3.31-3.05 (8H, br. m), 1.81(6H, s)

LCMS: m/z 505, 507 [M+H]⁺

Example 287 Compound F4-49-Bromo-8-{4-[2-(2-methoxy-ethoxy)-ethyl]-piperazin-1-yl}-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound F3-9 and1-bromo-2-(2-methoxyethoxy)ethane.

LCMS: m/z 551, 553 [M+H]⁺

HPLC retention time: 2.80 min (analysis condition W)

Example 288 Compound F4-59-Bromo-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F3-9 andtetrahydropyran-4-one.

LCMS: m/z 533, 535 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition W)

Example 289 Compound F4-69-Bromo-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-thiopyran-4-yl)-piperazin-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F3-9 andtetrahydrothiopyran-4-one.

LCMS: m/z 549, 551 [M+H]⁺

HPLC retention time: 2.86 min (analysis condition W)

Example 290 Compound F4-79-Bromo-8-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8,the title compound was prepared from Compound F4-6.

LCMS: m/z 581, 583 [M+H]⁺

HPLC retention time: 2.66 min (analysis condition W)

Example 291 Compound F4-89-Bromo-8-(4-cyclopropylmethyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound F3-9 andbromomethylcyclopropane.

LCMS: m/z 503, 505 [M+H]⁺

HPLC retention time: 2.81 min (analysis condition W)

Example 292 Compound F4-99-Bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F3-9 and(1-ethoxy-cyclopropoxy)-trimethyl-silane.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.22-8.30 (2H, m), 8.00 (1H, s), 7.56 (1H,d, J=7.9 Hz), 7.43 (1H, s), 3.30 (1H, d, J=5.8 Hz), 3.11 (4H, s), 2.75(4H, s), 1.75 (6H, s), 0.47 (2H, d, J=5.8 Hz), 0.34 (2H, d, J=5.8 Hz)

LCMS: m/z 489, 491 [M+H]⁺

HPLC retention time: 1.68 min (analysis condition S)

Example 293 Compound F4-109-Bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F3-9 and cyclobutanone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.23-8.29 (2H, m), 8.00 (1H, s), 7.55 (1H,d, 7.9 Hz), 7.45 (1H, s), 4.04-4.15 (1H, m), 3.10-3.20 (4H, m),2.39-2.48 (4H, m), 1.97-2.06 (2H, m), 1.78-1.88 (2H, m), 1.77 (6H, s),1.61-1.72 (2H, m)

LCMS: m/z 503, 505 [M+H]⁺

HPLC retention time: 2.78 min (analysis condition W)

Example 294 Compound F5-19-Ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound F3-3.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.78 (1H, s), 8.31 (1H, dd, J=8.1, 0.7Hz), 8.19 (1H, s), 8.02 (1H, dd, J=1.4, 0.7 Hz), 7.61 (1H, dd, J=8.2,1.4 Hz), 7.33 (1H, s), 4.55 (1H, s), 3.43 (4H, br), 2.98 (3H, s), 1.79(6H, s).

LCMS: m/z 473 [M+H]⁺

HPLC retention time: 2.27 min (analysis condition S)

Example 295 Compound F5-2N-[1-(3-Cyano-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound F4-2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.98 (1H, s), 8.30 (1H, d, J=8.1 Hz), 8.15(1H, s), 8.02 (1H, s), 7.61 (1H, d, J=7.9 Hz), 7.23 (2H, s+d), 4.55 (1H,s), 3.79 (2H, brd), 2.95 (4H, br), 1.96 (2H, brd), 1.78 (3H, s), 1.65(2H, brd).

LCMS: m/z 487 [M+H]⁺

HPLC retention time: 2.15 min (analysis condition S)

Example 296 Compound F5-36,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3,9-dicarbonitrile

Under the same conditions as the method for synthesizing Compound A5-2,the target compound was prepared from Compound F3-2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.33 (1H, d, J=1.3 Hz), 8.27 (1H, dd,J=7.7, 1.3 Hz), 8.00 (1H, s), 7.57 (1H, d, J=7.7 Hz), 7.40 (1H, s), 3.74(2H, m), 3.19-3.33 (1H, m), 2.98-3.12 (2H, m), 2.35-2.62 (2H, m),2.11-2.29 (2H, m), 1.89-2.06 (2H, m), 1.78 (6H, s), 1.54-1.70 (6H, m).

LCMS: m/z 464 [M+H]⁺

HPLC retention time: 1.55 min (analysis condition S)

Example 297 Compound F5-49-Ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1and Compound E4-2-2, the title compound was prepared from Compound F3-2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.29 (1H, d, J=8.2 Hz), 8.14 (1H, s), 8.00(1H, s), 7.58 (1H, dd, J=8.1, 1.3 Hz), 7.24 (1H, s), 4.50 (1H, s),3.70-3.83 (2H, m), 3.34-3.48 (1H, m), 2.83-2.98 (2H, m), 2.45-2.58 (2H,m), 2.10-2.23 (2H, m), 1.90-2.03 (2H, m), 1.76 (6H, s), 1.51-1.74 (6H,m).

LCMS: m/z 463 [M+H]⁺

HPLC retention time: 1.60 min (analysis condition S)

Example 298 Compound F5-59-Ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1and Compound E4-2-2, the title compound was prepared from Compound F3-4.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.82 (1H, s), 8.31 (1H, d, J=7.9 Hz), 8.18(1H, s), 8.02 (1H, s), 7.61 (1H, d, J=7.9 Hz), 7.28 (1H, s), 4.53 (1H,s), 3.80 (4 H, s), 3.36 (4H, s), 1.79 (6H, s).

LCMS: m/z 396 [M+H]⁺

HPLC retention time: 2.32 min (analysis condition S)

Example 299 Compound F5-69-(3-Dimethylamino-prop-1-ynyl)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F3-4 and3-dimethylaminopropyne.

¹H-NMR (270 MHz, CDCl₃) δ: 8.52 (1H, d, J=7.8 Hz), 8.47 (1H, s), 7.76(1H, s), 7.56 (1H, d, J=7.8 Hz), 7.03 (1H, s), 3.92 (4H, m), 3.55 (2H,s), 3.39 (4H, m), 2.37 (6H, s), 1.83 (6H, s)

LCMS: m/z 453 [M+H]⁺

Example 300 Compound F5-76,6-Dimethyl-8-morpholin-4-yl-9-(3-morpholin-4-yl-prop-1-ynyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To9-bromo-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound F3-4, 30 mg, 0.067 mmol), 3-bromopropyne (0.01 ml, 0.13 mmol),morpholine (0.029 ml, 0.33 mmol), X-Phos (4.8 mg, 15% mol), PdCl₂(CH₃CN)₂ (0.9 mg, 5% mol) and cesium carbonate (87 mg, 0.27 mmol),acetonitrile (2 ml) was added and the mixture was stirred at 80° C. for2 hr. The reaction solution was added to water, and then extracted withdichloromethane. The organic layer was dried over sodium sulfate. Thedrying agent was removed by filtration and the residues obtained afterconcentration under reduced pressure were purified by silica gel columnchromatography (dichloromethane/methanol) to obtain the target compound(pale brown solid, 18 mg, 64%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.29 (1H, d, J=7.8 Hz), 8.14 (1H, s), 8.00(1H, s), 7.59 (1H, d, J=7.8 Hz), 7.27 (1H, s), 3.79 (4H, m), 3.64 (4H,m), 3.61 (2H, s), 3.33 (4H, m), 2.56 (4H, m), 1.77 (6H, s)

LCMS: m/z 495 [M+H]⁺

Example 301 Compound F5-86,6-Dimethyl-8-morpholin-4-yl-11-oxo-9-pent-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F3-4 and1-pentyne.

LCMS: m/z 438 [M+H]⁺

HPLC retention time: 2.88 min (analysis condition S)

Example 302 Compound F5-99-(3-Methoxy-prop-1-ynyl)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F3-4 and3-methoxypropyne.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.30 (1H, d, J=7.8 Hz), 8.15 (1H, s), 8.01(1H, s), 7.60 (1H, d, J=7.8 Hz), 7.28 (1H, s), 4.41 (2H, s), 3.79 (4H,m), 3.37 (3H, s), 3.34 (4H, m), 1.78 (6H, s)

LCMS: m/z 440 [M+H]⁺

Example 303 Compound F5-109-[3-(4-Cyclopropyl-piperazin-1-yl)-prop-1-ynyl]-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-7,the title compound was prepared from Compound F3-4 and 3-bromopropyneand 4-cyclopropylpiperazine.

LCMS: m/z 534 [M+H]⁺

HPLC retention time: 1.40 min (analysis condition S)

Example 304 Compound F5-116,6-Dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F3-4 and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.29 (1H, d, J=7.8 Hz), 8.22 (1H, s), 8.09(1H, s), 7.99 (1H, s), 7.95 (1H, s), 7.56-7.61 (1H, m), 7.36 (1H, s),3.90 (3H, s), 3.73 (4H, s), 2.95 (4H, s), 1.77 (6H, s).

LCMS: m/z 452 [M+H]⁺

HPLC retention time: 2.18 min (analysis condition U)

Example 305 Compound F5-129-Cyclopropyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F3-4 and potassiumcyclopropyltrifluoroborate.

¹H-NMR (270 MHz, CD₃OD+CDCl₃) δ: 8.45 (1H, d, J=7.8 Hz), 7.83 (2H, m),7.54 (1H, d, J=7.8 Hz), 7.20 (1H, s), 3.96 (4H, m), 3.24 (4H, m), 2.25(1H, m), 1.80 (6H, s), 1.09 (2H, m), 0.93 (2H, m)

LCMS: m/z 412 [M+H]⁺

Example 306 Compound F5-136,6-Dimethyl-8-morpholin-4-yl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-24,the title compound was prepared from Compound F3-4 and potassiumvinyltrifluoroborate.

LCMS: m/z 398 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition U)

Example 307 Compound F5-149-Ethynyl-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound F3-8.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.73 (1H, s), 8.31 (1H, d, J=9.1 Hz), 8.16(1H, d, J=1.2 Hz), 8.00 (1H, s), 7.60 (1H, d, J=7.9 Hz), 7.25 (1H, s),4.50 (1H, d, J=1.8 Hz), 2.72 (1H, m), 2.65 (4H, s), 1.78 (6H, s), 1.04(6H, d, J=5.5 Hz).

LCMS: m/z 437 [M+H]⁺

HPLC retention time: 1.48 min (analysis condition S)

Example 308 Compound F5-15-14-(3-Cyano-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F3-10 andpotassium cyclopropyltrifluoroborate.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.55 (1H, s), 8.28-8.25 (1H, m), 7.98-7.95(1H, m), 7.62 (1H, s), 7.32 (1H, s), 3.56-3.53 (4 h, m), 3.09-3.07 (4H,m), 2.22-2.18 (1H, m), 1.73 (6H, br s), 1.44 (9H, s), 1.08-1.05 (2H, m),0.77-0.76 (2H, m)

LCMS: m/z 511 [M+H]⁺

HPLC retention time: 4.50 min (analysis condition W)

Example 309 Compound F5-15-29-Cyclopropyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound F5-15-1.

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition W)

Example 310 Compound F5-169-Ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound F4-3.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.77 (1H, br. s), 8.31 (1H, d, J=8.2 Hz),8.16 (1H, s), 8.02 (1H, s), 7.61 (1H, dd, J=8.2, 1.3 Hz), 7.27 (1H, s),4.59 (2H, dd, J=6.6, 6.6 Hz), 4.51 (1H, s), 4.49 (2H, dd, J=6.6, 6.6Hz), 3.51 (1H, t, J=6.6 Hz), 3.35-3.43 (4H, m), 2.43-2.50 (4H, s), 1.78(6H, s).

LCMS: m/z 451 [M+H]⁺

HPLC retention time: 1.40 min (analysis condition S)

Example 311 Compound F5-176,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3,9-dicarbonitrile

According to the same method as the method for synthesizing CompoundA5-2, the title compound was prepared from Compound F4-3.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.84 (1H, br. s), 8.36 (1H, s), 8.32-8.29(1H, d, 8.08 Hz), 8.04 (1H, s), 7.65-7.62 (1H, d, 8.08 Hz), 7.44 (1H,s), 4.62-4.57 (2H, m), 4.52-4.47 (2H, m), 3.81-3.78 (2H, t, 4.61 Hz),3.57-3.50 (1H, m), 3.43 (4H, m) 2.51 (4H, m), 1.80 (6H, s)

LCMS: m/z 452 [M+H]⁺

Example 312 Compound F5-189-(3-Methoxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-1-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 and3-methoxypropyne.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.77 (1H, br. s), 8.32-8.29 (1H, d, 8.08Hz), 8.13 (1H, s), 8.01 (1H, s), 7.62-7.59 (1H, d, 8.08 Hz), 7.27 (1H,s), 4.62-4.57 (2H, m), 4.52-4.47 (2H, m), 4.39 (2H, s), 3.53-3.47 (1H,m), 3.38 (4H, m), 3.36 (3H, s), 2.51 (4H, m), 1.77 (6H, s)

LCMS: m/z 495 [M+H]⁺

Example 313 Compound F5-199-(3-Dimethylamino-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 anddimethyl-prop-2-ynylamine.

LCMS: m/z 508 [M+H]⁺

HPLC retention time: 1.07 min (analysis condition S)

Example 314 Compound F5-206,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-9-[3-(4-oxetan-3-yl-piperazin-1-yl)-prop-1-ynyl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-7,the title compound was prepared from Compound F4-3, 3-bromopropyne and4-oxetan-3-yl-piperazine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.30 (1H, d, J=7.8 Hz), 8.12 (1H, s), 8.00(1H, s), 7.59 (1H, d, J=7.8 Hz), 7.26 (1H, s), 4.60-4.42 (8H, m), 3.61(2H, s), 3.60-3.30 (6H, m), 2.60-2.30 (12H, m), 1.77 (6H, s)

LCMS: m/z 605 [M+H]⁺

Example 315 Compound F5-219-Cyclopentylethynyl-6,6-dimethyl-8-(4-oxetan-3-ylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 andcyclopentylacetylene.

LCMS: m/z 519 [M+H]⁺

HPLC retention time: 1.80 min (analysis condition S)

Example 316 Compound F5-226,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 and propyne.

¹H-NMR (400 MHz, CD₃OD) δ: 8.37 (1H, d, J=8.2 Hz), 8.18 (1H, s), 7.84(1H, s), 7.53 (1H, d, J=8.2 Hz), 7.19 (1H, s), 4.70-4.77 (2H, m),4.62-4.68 (2H, m), 3.57-3.63 (1H, m), 3.38-3.45 (4H, m), 2.54-2.61 (4H,m), 2.10 (3H, s), 1.79 (6H, s)

LCMS: m/z 465 [M+H]⁺

HPLC retention time: 1.90 min (analysis condition U)

Example 317 Compound F5-239-(3-Hydroxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the TMS complex of the title compound was prepared from CompoundF4-3 and trimethylprop-2-ynyloxysilane. By treating the resulting TMScomplex with tetrabutylammonium fluoride, the title compound wasobtained.

LCMS: m/z 481 [M+H]⁺

HPLC retention time: 1.30 min (analysis condition S)

Example 318 Compound F5-246,6-Dimethyl-9-(4-methyl-pent-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 and4-methylpent-1-yne.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.75 (1H, br. s), 8.32-8.29 (1H, d, 8.08Hz), 8.08 (1H, s), 8.01 (1H, s), 7.62-7.59 (1H, m), 7.23 (1H, s),4.61-4.57 (2H, m), 4.51-4.46 (2H, m), 3.51-3.47 (1H, m), 3.37 (4H, m),2.46 (4H, m), 2.41-2.39 (2H, d, 5.94 Hz), 1.92-1.80 (1H, m), 1.77 (6H,s), 1.04 (3H, s), 1.01 (3H, s)

LCMS: m/z 507 [M+H]⁺

Example 319 Compound F5-259-Cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 andethynylcyclopropane.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.74 (1H, br. s), 8.32-8.29 (1H, d, 8.08Hz), 8.05 (1H, s), 8.00 (1H, s), 7.62-7.58 (1H, m), 7.21 (1H, s),4.62-4.57 (2H, m), 4.51-4.47 (2H, m), 3.53-3.48 (1H, m), 3.34 (4H, m),2.46 (4H, m), 1.76 (6H, s), 1.64-1.58 (1H, m), 0.97-0.89 (2H, m),0.76-0.70 (2H, m)

LCMS: m/z 491 [M+H]⁺

Example 320 Compound F5-266,6-Dimethyl-9-(3-morpholin-4-yl-prop-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-7,the title compound was prepared from Compound F4-3, 3-bromopropyne andmorpholine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.29 (1H, d, J=7.8 Hz), 8.13 (1H, s), 8.02(1H, s), 7.59 (1H, d, J=7.8 Hz), 7.25 (1H, s), 4.61-4.48 (4H, m),3.64-3.32 (11H, m), 2.60-2.40 (8H, m), 1.78 (6H, s)

LCMS: m/z 550 [M+H]⁺

Example 321 Compound F5-276,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-pent-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 and1-pentyne.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.72 (1H, br. s), 8.28 (1H, d, 8.1 Hz),8.06 (1H, s), 7.98 (1H, s), 7.58 (1H, d, 8.1 Hz), 7.21 (1H, s),4.60-4.43 (4H, m), 3.53-3.44 (1H, m), 3.39-3.32 (2H, m), 1.75 (6H, s),1.60-1.53 (4H, m), 1.01 (3H, t, 7.3 Hz)

LCMS: m/z 493 [M+H]⁺

HPLC retention time: 2.17 min (analysis condition U)

Example 322 Compound F5-286,6-Dimethyl-9-(5-methyl-hex-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 and5-methylhex-1-yne.

LCMS: m/z 521 [M+H]⁺

HPLC retention time: 2.37 min (analysis condition U)

Example 323 Compound F5-299-(3-Diethylamino-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 and3-diethylaminopropyne.

LCMS: m/z 536 [M+H]⁺

HPLC retention time: 1.13 min (analysis condition S)

Example 324 Compound F5-309-[3-(Benzyl-ethyl-amino)-prop-1-ynyl]-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 and3-benzyl-3-ethylaminopropyne.

LCMS: m/z 584 [M+H]⁺

HPLC retention time: 1.32 min (analysis condition S)

Example 325 Compound F5-319-[3-(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-prop-1-ynyl]-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-3 and3-(1,1-dioxo-1l6-thiomorpholin-4-yl)-propyne.

LCMS: m/z 598 [M+H]⁺

HPLC retention time: 1.35 min (analysis condition S)

Example 326 Compound F5-329-Isopropenyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F4-3 and2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane.

¹H-NMR (270 MHz, CD₃OD+CDCl₃) δ: 8.44 (1H, d, J=7.8 Hz), 8.09 (1H, s),7.83 (1H, s), 7.54 (1H, d, J=7.8 Hz), 7.18 (1H, s), 5.24-5.20 (2H, m),4.81-4.68 (4H, m), 3.66 (1H, m), 3.30 (4H, m), 2.57 (4H, m), 2.21 (3H,s), 1.82 (6H, s)

LCMS: m/z 467 [M+H]⁺

Example 327 Compound F5-336,6,9-Trimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-47,the title compound was prepared from Compound F4-3.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.71 (1H, br. s), 8.33-8.31 (1H, d, 8.08Hz), 8.01 (1H, s), 7.97 (1H, s), 7.62-7.59 (1H, m), 7.32 (1H, s),4.61-4.57 (2H, m), 4.51-4.47 (2H, m), 3.55-3.49 (1H, m), 3.05 (4H, m),2.47 (4H, m), 2.33 (3H, s), 1.76 (6H, s)

LCMS: m/z 441 [M+H]⁺

Example 328 Compound F5-349-Cyclopropyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F5-15-2 and oxetan-3-one.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.32-8.29 (1H, m), 8.00-7.99 (1H, m),7.62-7.58 (2H, m), 7.32-7.31 (1H, m), 4.61-4.57 (2H, m), 4.52-4.49 (2H,m), 3.53 (1H, br. s), 3.18 (4H, br. s), 1.75 (6H, s), 1.25-1.23 (1H, m),1.09-1.04 (2H, m), 0.79-0.75 (2H, m)

LCMS: m/z 467 [M+H]⁺

HPLC retention time: 2.74 min (analysis condition W)

Example 329 Compound F5-356,6-Dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F4-3 and1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-1H-pyrazole.

LCMS: m/z 507 [M+H]⁺

HPLC retention time: 1.75 min (analysis condition U)

Example 330 Compound F5-36-14-[3-Cyano-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazol-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F3-2.

LCMS: m/z 621 [M+H]⁺

HPLC retention time: 2.58 min (analysis condition U)

Example 331 Compound F5-36-26,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound F5-36-1.

LCMS: m/z 520 [M+H]⁺

HPLC retention time: 1.82 min (analysis condition U)

Example 332 Compound F5-378-(4-Cyclopropyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound F4-9.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.76 (1H, br. s), 8.31 (1H, d, J=8.1 Hz),8.15 (1H, s), 8.01 (1H, s), 7.61 (1H, dd, J=8.1, 1.5 Hz), 7.24 (1H, s),4.52 (1H, s), 3.28-3.36 (4H, m), 3.17 (1H, d, J=5.3 Hz), 2.70-2.77 (4H,m), 1.76 (6H, s), 0.47 (2H, d, J=5.3 Hz), 0.36 (2H, d, J=5.3 Hz).

LCMS: m/z 435 [M+H]⁺

HPLC retention time: 1.57 min (analysis condition S)

Example 333 Compound F5-388-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-9 and propyne.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.76 (1H, br. s), 8.31-8.28 (1H, d, 8.08Hz), 8.06 (1H, s), 8.00 (1H, s), 7.60-7.57 (1H, m), 7.19 (1H, s), 3.29(4H, m), 2.74 (4H, m), 2.55 (1H, m), 2.13 (3H, s), 1.75 (6H, s),0.51-0.43 (2H, m), 0.38-0.32 (2H, m)

LCMS: m/z 449 [M+H]⁺

Example 334 Compound F5-398-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-phenyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F4-9 andphenylboric acid.

LCMS: m/z 487 [M+H]⁺

HPLC retention time: 2.15 min (analysis condition U)

Example 335 Compound F5-408-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-pyridin-3-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F4-9 andpyridine-3-boric acid.

LCMS: m/z 488 [M+H]⁺

HPLC retention time: 1.53 min (analysis condition U)

Example 336 Compound F5-418-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-thiophene-2-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F4-9 andthiophene-2-boric acid.

LCMS: m/z 493 [M+H]⁺

HPLC retention time: 2.13 min (analysis condition U)

Example 337 Compound F5-428-(4-Cyclopropyl-piperazin-1-yl)-6,6,9-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-47,the title compound was prepared from Compound F4-9.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.71 (1H, br. s), 8.33-8.30 (1H, d, 8.08Hz), 8.00 (1H, s), 7.96 (1H, s), 7.61-7.58 (1H, m), 7.29 (1H, s), 2.97(4H, m), 2.73 (4H, m), 2.56 (1H, m), 2.34 (3H, s), 1.76 (6H, s),1.64-1.58 (1H, m), 0.50-0.44 (2H, m), 0.37-0.32 (2H, m)

LCMS: m/z 425 [M+H]⁺

Example 338 Compound F5-438-(4-Cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere, to the MeCN (8 ml) suspension of9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound F4-10, 200 mg, 0.397 mmol), ethynyltriisopropylsilane (268 mg,3.0 eq.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos)(39 mg, 0.2 eq.), Pd(CH₃CN)₂Cl₂ (11 mg, 0.1 eq.) and cesium carbonate(518 mg, 4.0 eq.) were added and the mixture was stirred and heatedunder reflux condition until the reaction is completed. Upon thecompletion of the reaction, distilled water was added to the reactionsolution, which was then extracted with ethyl acetate. The organic layerwas washed with brine and dried over sodium sulfate. The drying agentwas removed by filtration and the residues obtained after concentrationunder reduced pressure were purified by silica gel column chromatography(ethyl acetate/methanol) to obtain8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-[(triisopropylsilanyl)-ethynyl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(179 mg, 74%).

To the THF (6 ml) solution of the obtained compound (179 mg, 0.295mmol), 1 M THF solution (710 μl) of tetrabutylammonium fluoride wasadded and the mixture was stirred until the reaction is completed. Uponthe completion of the reaction, ethyl acetate was added to the reactionsolution, which was then washed with distilled water and dried oversodium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure were washedwith a mixture solvent of ethanol and distilled water to obtain thetitle compound (67 mg, 92%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.85 (1H, s), 8.31 (1H, d, 7.9 Hz), 8.20(1H, s), 8.03 (1H, s), 7.62 (1H, d, 7.9 Hz), 7.35 (1H, s), 4.62 (1H, s),3.94-4.03 (2H, m), 3.79-3.89 (1H, m), 3.48-3.54 (2H, m), 3.27-3.38 (2H,m), 2.96-3.16 (2H, m), 2.30-2.41 (2H, m), 2.16-2.26 (2H, m), 1.72-1.85(8H, m)

LCMS: m/z 449 [M+H]⁺

HPLC retention time: 2.69 min (analysis condition W)

Example 339 Compound F5-448-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-10 underpropyne gas atmosphere.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.71 (1H, s), 8.30 (1H, d, 7.9 Hz), 8.06(1H, s), 8.00 (1H, s), 7.59 (1H, d, 7.9 Hz), 7.20 (1H, s), 2.75-2.83(1H, m), 2.40-2.48 (4H, m), 2.11 (3H, s), 1.97-2.06 (2H, m), 1.76 (6H,s), 1.62-1.71 (2H, m)

LCMS: m/z 463 [M+H]⁺

HPLC retention time: 2.80 min (analysis condition W)

Example 340 Compound F5-459-Cyclobutylethynyl-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F4-10 andethynylcyclobutane.

LCMS: m/z 503 [M+H]⁺

HPLC retention time: 1.85 min (analysis condition S)

Example 341 Compound F5-468-(4-Cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F5-15-2 and cyclobutanone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.23 (1H, d, 8 Hz), 7.92 (1H, br. s), 7.59(1H, s), 7.47 (1H, br. d, 8 Hz), 7.28 (1H, s), 3.12 (4H, br. s), 2.80(1H, dddd, 8, 8, 8, 8 Hz), 2.20-2.13 (1H, m), 2.01 (2H, br. s),1.86-1.68 (10H, m), 1.05 (2H, d, 8 Hz), 0.76 (2H, d, 4 Hz)

LCMS: m/z 465 [M+H]⁺

HPLC retention time: 2.79 min (analysis condition W)

Hydrochloric Acid Salt of Compound F5-46

8-(4-Cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilewas added with DMSO and 6 N hydrochloric acid (1.05 eq.) and dissolvedtherein. After freeze-drying, crystallization was performed by usingethanol comprising 25% water to obtain monohydrochloric acid salt of8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.81 (1H, s), 10.64 (1H, br. s), 8.32-8.29(1H, m), 8.01 (1H, s), 7.67 (1H, s), 7.61-7.60 (1H, m), 7.33 (1H, s),4.00-3.39 (6H, m), 3.28-3.02 (3H, m), 2.45-2.05 (5H, m), 1.83-1.77 (8H,m), 1.09-1.07 (2H, m), 0.81-0.80 (2H, m)

LCMS: m/z 465 [M+H]⁺

Example 342 Compound F5-478-(4-Cyclobutyl-piperazin-1-yl)-6,6,9-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere, to the N,N-dimethyl formamide (1.5 ml)solution of9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound F4-10, 50 mg, 0.099 mmol), trimethyl boroxine (12 mg, 0.1eq.), tetrakis triphenylphosphine palladium (39 mg, 0.2 eq.), andpotassium carbonate (41 mg, 3.0 eq.) were added, and the mixture wasstirred at 100° C. for 24 hr. Upon the completion of the reaction,distilled water was added to the reaction solution, which was thenextracted with ethyl acetate. The organic layer was washed with brineand dried over sodium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/methanol) to obtain the title compound (25 mg, 58%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.67 (1H, s), 8.31 (1H, d, 7.9 Hz), 7.98(1H, s), 7.95 (1H, s), 7.59 (1H, d, 7.9 Hz), 7.30 (1H, s), 2.96-3.04(4H, m), 2.76-2.84 (1H, m), 2.39-2.48 (4H, m), 2.32 (3H, s), 1.78-1.87(2H, m), 1.75 (6H, s), 1.63-1.71 (2H, m)

LCMS: m/z 439 [M+H]⁺

HPLC retention time: 2.66 min (analysis condition W)

Example 343 Compound F5-488-(4-Cyclobutyl-piperazin-1-yl)-9-isopropenyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-7-1, the title compound was prepared from Compound F4-10 and2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2] dioxaborolane.

LCMS: m/z 465 [M+H]⁺

HPLC retention time: 1.63 min (analysis condition S)

Example 344 Compound F5-499-Ethynyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound F3-11.

LCMS: m/z 479 [M+H]⁺

HPLC retention time: 1.90 min (analysis condition U)

Example 345 Compound F5-506,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound F3-11 and propynegas.

¹H-NMR (270 MHz, CD₃OD+CDCl₃) δ: 8.40 (1H, d, J=7.8 Hz), 8.24 (1H, s),7.84 (1H, s), 7.54 (1H, d, J=7.8 Hz), 7.14 (1H, s), 4.01-3.96 (2H, m),3.78 (4H, m), 2.88-2.84 (2H, m), 2.68 (4H, m), 2.16-1.73 (5H, m), 2.16(3H, s), 1.80 (6H, s)

LCMS: m/z 493 [M+H]⁺

Example 346 Compound F5-516,6,9-Trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-47,the title compound was prepared from Compound F3-11

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.70 (1H, br. s), 8.33-8.30 (1H, d, 8.08Hz), 8.00 (1H, s), 7.95 (1H, s), 7.61-7.58 (1H, m), 7.28 (1H, s), 3.60(4H, m), 3.32-3.26 (2H, m), 2.79-2.69 (2H, m), 2.32 (3H, s), 1.95-1.90(2H, m), 1.74 (6H, s), 1.65-1.52 (2H, m),

LCMS: m/z 469 [M+H]⁺

Methanesulfonic Acid Salt of Compound F5-51

6,6,9-Trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilewas added with DMSO and 2 N methanesulfonic acid (1.05 eq.) anddissolved therein. After freeze-drying, crystallization was performedwith ethanol to obtain methanesulfonic acid salt of6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.72 (1H, br. s), 9.60 (1H, br. s),8.33-8.31 (1H, d, 9.8 Hz), 8.01 (1H, s), 7.99 (1H, s), 7.61-7.59 (1H,m), 7.31 (1H, s), 4.07-4.04 (2H, m), 3.73-3.67 (2H, m), 3.55-3.40 (8H,m), 3.32-3.26 (1H, m), 2.70-2.60 (2H, m), 2.34 (3H, s), 2.30 (3H, s),1.95-1.90 (2H, m), 1.75 (6H, s)

LCMS: m/z 469 [M+H]⁺

Example 347 Compound F6-19-(1-Isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound F5-36-2 and acetone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.68 (1H, br. s), 8.30 (1H, d, 8.1 Hz),7.98 (1H, s), 7.82 (1H, s), 7.58 (1H, d, 8.1 Hz), 7.20 (1H, s), 5.85(1H, s), 3.56-3.44 (2H, m), 3.21-3.14 (2H, m), 2.77-2.66 (5H, m),2.12-2.09 (1H, m), 1.98-1.88 (2H, m), 1.74 (6H, s), 1.70-1.63 (1H, m),1.58-1.45 (2H, m), 1.09-1.00 (6H, m)

LCMS: m/z 563 [M+H]⁺

HPLC retention time: 1.90 min (analysis condition U)

Example 348 Compound F6-29-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound F5-36-2.

LCMS: m/z 598 [M+H]⁺

HPLC retention time: 1.52 min (analysis condition S)

Example 349 Compound F6-39-[3-(4-Cyclopropyl-piperazin-1-yl)-propyl]-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-10.

LCMS: m/z 538 [M+H]⁺

HPLC retention time: 1.32 min (analysis condition S)

Example 350 Compound F6-49-Ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-16.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.70 (1H, br. s), 8.29 (1H, d, 8.0 Hz),8.03-7.94 (2H, m), 7.59-7.55 (1H, m), 7.38 (1H, s), 4.59-4.47 (4H, m),3.53-5.47 (1H, m), 3.03-2.97 (2H, m), 2.73-2.62 (2H, m), 1.74 (6H, s),1.29-1.98 (3H, m)

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 1.92 min (analysis condition U)

Hydrochloric Acid Salt of Compound F6-4

9-Ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilewas added with DMSO and 6 N hydrochloric acid (1.05 eq.) and dissolvedtherein. After freeze-drying, crystallization was performed with ethanolcomprising 25% water to obtain monohydrochloric acid salt of9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.83 (1H, br. s), 11.59 (1H, br. s),8.33-8.31 (1H, m), 8.09 (1H, s), 8.02 (1H, s), 7.63-7.61 (1H, m), 7.39(1H, s), 4.91-4.60 (4H, br. m), 3.58-3.40 (1H, m), 3.31-3.05 (8H, br.m), 2.73 (2H, q, J=7.3), 1.81 (6H, s), 1.29 (3H, t, J=7.3)

LCMS: m/z 455 [M+H]⁺

Example 351 Compound F6-59-(3-Methoxy-propyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-18.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.73 (1H, br. s), 8.33-8.30 (1H, d, 8.08Hz), 8.01 (1H, s), 8.00 (1H, s), 7.62-7.59 (1H, d, 8.08 Hz), 7.42 (1H,s), 4.61-4.56 (2H, m), 4.51-4.46 (2H, m), 3.53-3.47 (1H, m), 3.42-3.37(2H, m), 3.02 (4H, m), 2.75-2.68 (2H, m), 2.51 (4H, m), 1.93-1.82 (2H,m), 1.76 (6H, s)

LCMS: m/z 499 [M+H]⁺

Example 352 Compound F6-66,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-9-[3-(4-oxetan-3-yl-piperazin-1-yl)-propyl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-20.

LCMS: m/z 609 [M+H]⁺

HPLC retention time: 1.00 min (analysis condition S)

Example 353 Compound F6-79-(2-Cyclopentyl-ethyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-21.

LCMS: m/z 523 [M+H]⁺

HPLC retention time: 1.92 min (analysis condition S)

Example 354 Compound F6-86,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-22.

¹H-NMR (270 mHz DMSO-d₆) δ: 12.75 (1H, s), 8.30 (1H, d, J=8.2 Hz),8.01-7.97 (2H, m), 7.59 (1H, d, J=7.1 Hz), 7.38 (1H, s), 4.51 (4H, dt,J=27.7, 6.3 Hz), 3.55-3.49 (1H, m), 3.02-2.96 (4H, m), 2.63 (2H, t,J=7.3 Hz), 2.47-2.41 (4H, m), 1.73 (6H, s), 1.70-1.61 (2H, m), 0.94 (3H,t, J=7.4 Hz).

LCMS: m/z 469 [M+H]⁺

HPLC retention time: 1.57 min (analysis condition S)

Example 355 Compound F6-98-[4-(4-Hydroxy-butyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound F6-8.

LCMS: m/z 485 [M+H]⁺

HPLC retention time: 1.61 min (analysis condition S)

Example 356 Compound F6-109-(3-Hydroxy-propyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-23.

LCMS: m/z 499 [M+H]⁺

HPLC retention time: 1.42 min (analysis condition S)

Example 357 Compound F6-116,6-Dimethyl-9-(3-morpholin-4-yl-propyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-26.

LCMS: m/z 554 [M+H]⁺

HPLC retention time: 1.50 min (analysis condition U)

Example 358 Compound F6-126,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-pentyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-27.

LCMS: m/z 497 [M+H]⁺

HPLC retention time: 2.25 min (analysis condition U)

Example 359 Compound F6-139-(3-Isopropoxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound F5-23 and 2-bromopropane.

¹H-NMR (270 MHz, CD₃OD+CDCl₃) δ: 8.40 (1H, d, J=7.8 Hz), 8.32 (1H, s),7.84 (1H, s), 7.53 (1H, d, J=7.8 Hz), 7.18 (1H, s), 4.80-4.68 (4H, m),4.46 (2H, s), 3.95 (1H, m), 3.64 (1H, m), 3.46 (4H, m), 2.62 (4H, m),1.82 (6H, s), 1.24 (6H, d, J=7.0 Hz)

LCMS: m/z 523 [M+H]⁺

Example 360 Compound F6-149-Isopropyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-32.

¹H-NMR (270 MHz, CD₃OD+CDCl₃) δ: 8.44 (1H, d, J=7.8 Hz), 8.27 (1H, s),7.84 (1H, s), 7.54 (1H, d, J=7.8 Hz), 7.36 (1H, s), 4.82-4.70 (4H, m),3.68 (1H, m), 3.45 (1H, m), 3.13-3.09 (4H, m), 2.64-2.62 (4H, m), 1.81(6H, s), 1.31 (6H, d, J=7.0 Hz)

LCMS: m/z 469 [M+H]⁺

Example 361 Compound F6-158-(4-Cyclopropyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-37.

LCMS: m/z 439 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition U)

Example 362 Compound F6-168-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-38.

LCMS: m/z 453 [M+H]⁺

HPLC retention time: 1.63 min (analysis condition S)

Example 363 Compound F6-178-(4-Cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-43.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.80 (1H, s), 8.32 (1H, d, 7.9 Hz), 8.10(1H, s), 8.02 (1H, s), 7.62 (1H, d, 7.9 Hz), 7.38 (1H, s), 3.78-3.88(1H, m), 3.79-3.89 (1H, m), 3.48-3.54 (2H, m), 3.40- 3.47 (2H, m),3.30-3.39 (2H, m), 3.02-3.24 (4H, m), 2.73 (2H, q, 7.3 Hz), 2.30-2.41(2H, m), 2.17-2.26 (2H, m), 1.71-1.86 (8H, m), 1.29 (3H, t, 7.3 Hz)

LCMS: m/z 453 [M+H]⁺

HPLC retention time: 2.76 min (analysis condition W)

Methanesulfonic Acid Salt of Compound F6-17

8-(4-Cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilewas dissolved in 6 volumes of DMF at room temperature and added dropwisewith aqueous solution of methanesulfonic acid (2 M, 1.05 eq.). Theresulting solution was added dropwise to 60 volumes of acetonitrile, andthe precipitated solid was filtered and dried to obtainmonomethanesulfonic acid salt of8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.75 (1H, s), 8.31 (1H, J=8.4 Hz), 8.07(1H, s), 8.01 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.38 (1H, s), 3.58-2.84(10H, m), 2.71 (2H, q, J=7.5 Hz), 2.34 (3H, s), 2.20-2.04 (4H, m),1.76-1.68 (8H, m), 1.26 (3H, t, J=7.5 Hz) FABMS: m/z 453 [M+H]⁺

Example 364 Compound F6-188-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-44.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.69 (1H, s), 8.31 (1H, d, 7.9 Hz), 8.01(1H, s), 7.99 (1H, s), 7.60 (1H, d, 7.9 Hz), 7.39 (1H, s), 2.92-3.02(4H, m), 2.75-2.84 (1H, m), 2.65 (2H, t, 7.3 Hz), 2.38-2.48 (4H, m),1.96-2.06 (2H, m), 1.78-1.87 (2H, m), 1.75 (6H, s), 1.62-1.73 (4H, m),0.97 (3H, t, 7.3 Hz)

LCMS: m/z 467 [M+H]⁺

HPLC retention time: 2.96 min (analysis condition W)

Example 365 Compound F6-198-(4-Cyclobutyl-piperazin-1-yl)-9-isopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13,the title compound was prepared from Compound F5-48.

LCMS: m/z 467 [M+H]⁺

HPLC retention time: 1.67 min (analysis condition S)

Example 366 Compound F6-209-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-49.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.70 (1H, s), 8.32 (1H, d, J=7.9 Hz), 8.04(1H, s), 8.00 (1H, s), 7.61 (1H, d, J=8.5 Hz), 7.34 (1H, s), 3.64-3.57(4H, m), 3.27-3.18 (2H, m), 2.82-2.66 (4H, m), 2.39-2.28 (1H, m),1.96-1.87 (2H, m), 1.76 (6H, s), 1.69-1.53 (2H, m), 1.29 (3H, t, J=7.3Hz)

LCMS: m/z 483 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition U)

Hydrochloric Acid Salt of Compound F6-20

9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilewas dissolved in a mixture solution of methylethyl ketone (10 volumes),water (4 volumes) and acetic acid (3 volumes) at 60° C. To the dissolvedsolution, hydrochloric acid (2 N) was added dropwise (1 volume). Afterstirring at 60° C. for 30 min, ethanol (25 volume) was added dropwise.The precipitated solid was filtered and dried to obtain monohydrochloricacid salt of9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.78 (1H, s), 10.57 (1H, br. s), 8.30 (1H,J=8.4 Hz), 8.05 (1H, s), 7.99 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.36 (1H,s), 4.02-3.99 (2H, m), 3.84-3.78 (2H, m), 3.51-3.48 (2H, m), 3.15-3.13(1H, s), 2.83-2.73 (2H, s), 2.71-2.67 (2H, s), 2.23-2.20 (2H, m),1.94-1.83 (2H, m), 1.75 (6H, s), 1.27 (3H, t, J=7.5 Hz)

FABMS: m/z 483 [M+H]⁺

Example 367 Compound F6-216,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound F5-50.

¹H-NMR (270 MHz, CD₃OD+CDCl₃) δ: 8.41 (1H, d, J=7.8 Hz), 8.14 (1H, s),7.84 (1H, s), 7.53 (1H, d, J=7.8 Hz), 7.31 (1H, s), 3.77 (4H, m), 3.32(2H, m), 2.86-2.66 (8H, m), 2.43-2.05 (3H, m), 1.79 (6H, s), 1.79-1.66(4H, m), 1.02 (3H, t, J=7.3 Hz)

LCMS: m/z 497 [M+H]⁺

Example 368 Compound G28-Methoxy-10,10-dimethyl-10,11-dihydro-5H-1,11-diaza-benzo[B]fluorene

2-Hydrazinopyridine (1.3 g, 11.8 mmol) and7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.4g, 11.8 mmol) were dissolved in NMP (60 mL), and stirred at 190° C. for48 hr. The reaction solution was diluted with ethyl acetate, washed withwater and dried over magnesium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (hexane/ethylacetate) to obtain the target compound (white solid, 101 mg, 3%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 11.53 (1H, s), 8.16-8.12 (1H, m), 7.84 (1H,d, J=7.8 Hz), 7.23 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.03-6.98 (1H, m),6.85-6.81 (1H, m), 3.96 (2H, s), 3.77 (3H, s), 1.64 (6H, s)

LCMS: m/z 279 [M+H]⁺

HPLC retention time: 2.08 min (analysis condition U)

Example 369 Compound G38-Methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound G2.

¹H-NMR (400 MHz, CDCl₃) δ: 12.95 (1H, br. s), 8.78 (1H, d, J=7.8 Hz),8.52 (1H, d, J=4.9 Hz), 8.41 (1H, d, J=8.8 Hz), 7.37 (1H, dd, J=7.7, 5.0Hz), 7.15 (1H, s), 7.04-7.00 (1H, m), 3.94 (3H, s), 1.98 (6H, s)

LCMS: m/z 293 [M+H]⁺

HPLC retention time: 2.13 min (analysis condition U)

Example 370 Compound G48-Hydroxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound G3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.66 (1H, d, J=7.7 Hz), 8.29 (1H, d, J=4.9Hz), 8.23 (1H, d, J=13.8 Hz), 7.29 (1H, dd, J=7.7, 5.0 Hz), 7.12 (1H,s), 6.93 (1H, d, J=8.6 Hz), 1.71 (6H, s)

LCMS: m/z 279 [M+H]⁺

HPLC retention time: 1.72 min (analysis condition U)

Example 371 Compound G5 Trifluoro-methanesulfonic Acid10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-ylester

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound G4.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, d, J=7.8 Hz), 8.60-8.52 (2H, m),7.55 (1H, s), 7.46-7.40 (2H, m), 2.01 (6H, s)

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 1.75 min (analysis condition U)

Example 372 Compound G610,10-Dimethyl-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound G5 and4-pyrrolidin-1-yl-piperidine.

¹H-NMR (400 MHz, CDCl₃) δ: 13.12 (1H, s), 8.78 (1H, d, J=7.8 Hz), 8.49(1H, d, J=4.9 Hz), 8.29 (1H, d, J=8.8 Hz), 7.34 (1H, dd, J=7.7, 5.0 Hz),7.06-6.98 (2H, m), 3.96-3.88 (2H, m), 3.02-3.92 (2H, m), 2.69-2.60 (4H,m), 2.32-2.23 (1H, m), 2.09-2.00 (4H, m), 1.92 (6H, s), 1.26-1.19 (4H,m)

LCMS: m/z 415 [M+H]⁺

HPLC retention time: 1.57 min (analysis condition U)

Example 373 Compound H16-Acetyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

To the dichloromethane (70 ml) solution of7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 3g, 14.7 mmol), acetic anhydride (1.7 ml, 1.2 eq.) and aluminumchloride-nitrobenzene solution (1 M, 44 ml, 3 eq.) was added at 0° C.,and stirred for 3 hr. Thereafter, the reaction solution was added withsaturated aqueous solution of sodium hydrogen carbonate and extractedtwice with dichloromethane. The organic layer was washed with brine anddried over magnesium sulfate. The drying agent was removed by filtrationand the residues obtained after concentration under reduced pressurewere purified by silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound as a crude product.

Example 374 Compound H2-11-(3-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-ethanone

Under the same conditions as the method for synthesizing Compound A3-1,the title compound was prepared from Compound H1 and(3-bromo-phenyl)-hydrazine.

LCMS: m/z 398 [M+H]⁺

HPLC retention time: 3.97 min (analysis condition Y)

Example 375 Compound H2-21-(1-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-ethanone

The title compound was obtained as a by-product of the synthesis ofCompound H2-1.

LCMS: m/z 398 [M+H]⁺

HPLC retention time: 3.97 min (analysis condition Y)

Example 376 Compound H39-Acetyl-3-bromo-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound H2.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.80 (6H, s), 2.58 (3H, s), 4.06 (3H, s),7.38 (1H, dd, 8.39 Hz, 1.91 Hz), 7.51 (1H, s), 7.67 (1H, bs, 1.53 Hz),8.10 (1H, d, 8.39 Hz), 8.41 (1H, s), 12.3 (1H, s)

LCMS: m/z 412, 414 [M+H]⁺

HPLC retention time: 2.73 min (analysis condition U)

Example 377 Compound H49-Acetyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA5-2, the title compound was prepared from Compound H3.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.83 (6H, s), 2.58 (3H, s), 4.07 (3H, s),7.53 (1H, s), 7.61 (1H, d, 8.01 Hz), 8.03 (1H, s), 8.31 (1H, d, 8.77Hz), 8.42 (1H, s), 12.8 (1H, s).

LCMS: m/z 359 [M+H]⁺

HPLC retention time: 2.47 min (analysis condition U)

Example 378 Compound H59-Acetyl-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound H4.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.77 (6H, s), 2.75 (3H, s), 7.43 (1H, s),7.63 (1H, d, 8.01 Hz), 8.02 (1H, s), 8.32 (1H, d, 8.01 Hz), 8.67 (1H,s), 12.2 (1H, s), 12.8 (1H, s).

LCMS: m/z 345 [M+H]⁺

HPLC retention time: 2.27 min (analysis condition S)

Example 379 Compound H6-19-Acetyl-6,6-dimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound H5 andtetrahydropyran-4-ol.

LCMS: m/z 429 [M+H]⁺

HPLC retention time: 2.48 min (analysis condition U)

Example 380 Compound H6-29-Acetyl-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound H5.

LCMS: m/z 444 [M+H]⁺

HPLC retention time: 2.05 min (analysis condition U)

Example 381 Compound H7 Trifluoro-methanesulfonic Acid9-acetyl-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylester

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound H5.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.83 (6H, s), 2.74 (3H, s), 7.68 (1H, dd,8.01 Hz, 1.53 Hz), 8.08 (2H, s), 8.33 (1H, d, 8.77 Hz), 8.79 (1H, s),12.9 (1H, s).

Example 382 Compound H8-19-Acetyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound H7 and4-pyrrolidin-1-yl-piperidine.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.65 (2H, m), 1.69 (4H, s), 1.79 (6H, s),1.95 (2H, m), 2.18 (1H, m), 2.54 (4H, s), 2.59 (3H, s), 2.93 (2H, t,11.8 Hz), 3.37 (2H, m), 7.36 (1H, s), 7.60 (1H, d, 8.01), 8.01 (1H, s),8.13 (1H, s), 8.30 (1H, d, 8.39), 12.7 (1H, s).

LCMS: m/z 481 [M+H]⁺

HPLC retention time: 2.03 min (analysis condition U)

Example 383 Compound H8-29-Acetyl-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound H7.

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 2.02 min (analysis condition U)

Example 384 Compound H8-39-Acetyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound H7 and morpholine.

LCMS: m/z 414 [M+H]⁺

HPLC retention time: 2.11 min (analysis condition S)

Example 385 Compound H8-49-Acetyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound H7 and4-piperidin-4-yl-morpholine.

LCMS: m/z 497 [M+H]⁺

HPLC retention time: 1.45 min (analysis condition S)

Example 386 Compound H8-59-Acetyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound H7 and piperazine.

LCMS: m/z 413 [M+H]⁺

HPLC retention time: 1.71 min (analysis condition U)

Example 387 Compound H9-19-Acetyl-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound H8-5 and cyclobutanone.

LCMS: m/z 467 [M+H]⁺

HPLC retention time: 1.82 min (analysis condition U)

Example 388 Compound H9-29-Acetyl-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound H8-5 andtetrahydropyran-4-one.

LCMS: m/z 497 [M+H]⁺

HPLC retention time: 1.76 min (analysis condition U)

Example 389 Compound H9-39-Acetyl-8-[4-(1,1-dimethyl-prop-2-ynyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the anhydrous THF solution (0.5 mL) of9-acetyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound H8-5, 25 mg, 0.06 mmol), 3-chloro-3-methyl-but-1-yne (0.013mL, 0.12 mmol), copper (I) chloride (0.6 mg, 0.006 mmol) andtriethylamine (0.017 mL, 0.12 mmol) were added at room temperature.After stirring for 30 min, the mixture was added with water andextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate. The drying agent was removed by filtration and the residuesobtained after concentration under reduced pressure were purified byamino silica gel column chromatography (dichloromethane/methanol) toobtain the title compound (white solid, 9.8 mg, 35%).

LCMS: m/z 479 [M+H]⁺

HPLC retention time: 1.88 min (analysis condition U)

Example 390 Compound I1-16-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,3.37 g, 16.5 mmol) was dissolved in CH₃CN (82 mL), added with NCS (2.42g, 1.1 eq.) and stirred at 90° C. for 1.5 hr. The reaction solution wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over sodium sulfate. The drying agent wasremoved and the target compound was obtained after concentration underreduced pressure (yellow oily substance, 4.45 g).

¹H-NMR (400 MHz, CDCl₃) δ: 7.16 (1H, s), 6.85 (1H, s), 3.90 (3H, s),3.00 (2H, t, J=6.8 Hz), 2.65 (2H, t, J=6.8 Hz), 1.42 (6H, s).

LCMS: m/z 239 [M+H]⁺

HPLC retention time: 2.80 min (analysis condition U)

Example 391 Compound I1-29-Chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(Compound 11-1, 4.45 g, 16.5 mmol) and 3-hydrazinobenzonitrile (2.63 g,1.2 eq.) were dissolved in TFA (91 mL), and stirred at 90° C. for 3 hr.According to the concentration under reduced pressure, TFA was removedand the residues were added with saturated aqueous solution of NaHCO₃,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine and dried over sodium sulfate. The drying agent wasremoved by filtration and the residues obtained after concentrationunder reduced pressure were added with ethyl acetate. After stirring atroom temperature, the precipitated solid was separated by filtration.The filtrate was concentrated under reduced pressure to obtain the titlecompound as a mixture with 11-3 (red powder, 6.46 g).

Example 392 Compound I1-39-Chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound I1-2.

¹H-NMR (400 MHz, DMSO-d₆) δ: 11.66 (1H, s), 7.65-7.69 (1H, m), 7.44-7.48(1H, m), 7.39 (1H, s), 7.29 (1H, s), 7.17-7.23 (1H, m), 4.21 (2H, s),3.91 (3H, s), 1.69 (6H, s).

LCMS: m/z 337 [M+H]⁺

HPLC retention time: 3.15 min (analysis condition U)

Example 393 Compound I2-12-(4-Chloro-3-methoxy-phenyl)-2-methyl-propionitrile

1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) andisobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL),added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C.for 2 hr. The reaction solution was cooled to room temperature, addedwith aqueous solution of 1 N hydrochloric acid and then extracted withMTBE. The organic layer was washed with saturated brine and dried overmagnesium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (hexane/ethyl acetate) toobtain the title compound (1.72 g, 31%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.37 (1H, d, J=8.4 Hz), 7.05 (1H, d, J=2.1Hz), 6.97 (1H, dd, J=8.2, 2.1 Hz), 3.95 (3H, s), 1.73 (6H, s).

HPLC retention time: 2.33 min (analysis condition S)

Example 394 Compound I2-24-(4-Chloro-3-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl ester

Under the same conditions as the method for synthesizing Compound K3,the title compound was prepared from Compound I2-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 7.42 (1H, d, J=8.1 Hz), 6.92 (1H, d, J=2.1Hz), 6.86 (1H, dd, J=8.2, 2.3 Hz), 4.01 (2H, q, J=7.1 Hz), 3.87 (3H, s),3.43 (2H, s), 1.44 (6H, s), 1.12 (3H, t, J=7.2 Hz).

LCMS: m/z 299, 301 [M+H]⁺

HPLC retention time: 2.52, 3.05 min (analysis condition S)

Example 395 Compound I2-34-(4-Chloro-3-methoxy-phenyl)-2-(4-cyano-2-nitro-phenyl)-4-methyl-3-oxo-pentanoicAcid Ethyl Ester

Under the same conditions as the method for synthesizing Compound K4,the title compound was obtained as a crude product from Compound I2-2.

Example 396 Compound I2-42-[1-(4-Chloro-3-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carboxylicacid ethyl ester

Under the same conditions as the method for synthesizing Compound K5,the title compound was obtained from Compound I2-3.

LCMS: m/z 397, 399 [M+H]⁺

HPLC retention time: 2.83 min (analysis condition S)

Example 397 Compound I39-Chloro-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

(Method 1) Under the same conditions as the method for synthesizingCompound A4, the title compound was obtained from Compound I1-2.

(Method 2) Under the same conditions as the method for synthesizingCompound L8-1, the title compound was obtained from Compound I2-4.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.79 (1H, s), 8.27-8.31 (1H, m), 8.12 (1H,s), 8.00-8.02 (1H, m), 7.58-7.63 (1H, m), 7.51 (1H, s), 4.03 (3H, s),1.80 (6H, s).

LCMS: m/z 351 [M+H]⁺

HPLC retention time: 2.87 min (analysis condition U)

Example 398 Compound I49-Chloro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound I3.

LCMS: m/z 337 [M+H]⁺

HPLC retention time: 2.47 min (analysis condition U)

Example 399 Compound I5 Trifluoro-methanesulfonic Acid9-chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylester

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound I4.

LCMS: m/z 469 [M+H]⁺

HPLC retention time: 3.40 min (analysis condition U)

Example 400 Compound I6-19-Chloro-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound I5 and4-pyrrolidin-1-yl-piperidine.

LCMS: m/z 473 [M+H]⁺

HPLC retention time: 2.25 min (analysis condition U)

Example 401 Compound I6-29-Chloro-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound I5.

LCMS: m/z 447 [M+H]⁺

HPLC retention time: 2.30 min (analysis condition U)

Example 402 Compound I6-39-Chloro-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from 15 and morpholine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.79 (1H, s), 8.28 (1H, d, 8.0 Hz), 8.09(1H, s), 8.00 (1H, s), 7.59 (1H, d, 8.0 Hz), 7.45 (1H, s), 3.75-3.81(4H, m), 3.13-3.19 (4H, m), 1.76 (6H, s)

LCMS: m/z 406 [M+H]⁺

HPLC retention time: 2.88 min (analysis condition U)

Example 403 Compound I6-49-Chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound I5 and4-piperidin-4-yl-morpholine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.75 (1H, s), 8.28 (1H, d, 8.0 Hz), 8.07(1H, s), 8.00 (1H, s), 7.59 (1H, d, 8.0 Hz), 7.41 (1H, s), 3.55-3.62(4H, m), 3.47-3.56 (4H, m), 2.75-2.86 (2H, m), 2.45- 2.55 (4H, m),2.28-2.39 (1H, m), 1.86-1.96 (2H, m), 1.76 (6H, s), 1.52-1.66 (2H, m)

LCMS: m/z 489 [M+H]⁺

HPLC retention time: 1.97 min (analysis condition U)

Example 404 Compound I6-5-1[1-(9-Chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-carbamicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound I5 andpiperidin-4-yl-carbamic acid tert-butyl ester.

LCMS: m/z 519 [M+H]⁺

HPLC retention time: 3.27 min (analysis condition U)

Example 405 Compound I6-5-28-(4-Amino-piperidin-1-yl)-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound I6-5-1.

LCMS: m/z 419 [M+H]⁺

HPLC retention time: 2.12 min (analysis condition U)

Example 406 Compound I6-69-Chloro-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound I5 and piperazine.

LCMS: m/z 405 [M+H]⁺

HPLC retention time: 1.87 min (analysis condition U)

Example 407 Compound I7-1N-[1-(9-Chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound I6-5-2.

LCMS: m/z 497 [M+H]⁺

HPLC retention time: 2.62 min (analysis condition U)

Example 408 Compound I7-29-Chloro-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound I5 and1-oxetan-3-yl-piperazine.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.78 (1H, s), 8.27-8.31 (1H, m), 8.07-8.09(1H, s), 7.99-8.02 (1H, m), 7.59-7.62 (1H, m), 7.44-7.46 (1H, s),4.54-4.60 (2H, m), 4.44-4.51 (2H, m), 3.47-3.55 (1H, m), 3.16-3.24 (4H,m), 2.40-2.55 (4H, m), 1.77 (6H, s)

LCMS: m/z 461 [M+H]⁺

HPLC retention time: 2.13 min (analysis condition U)

Example 409 Compound I7-39-Chloro-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound I5 and1-cyclopropylpiperazine.

LCMS: m/z 445 [M+H]⁺

HPLC retention time: 1.97 min (analysis condition U)

Example 410 Compound I7-49-Chloro-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound I6-6 and cyclobutanone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.78 (1H, s), 8.29 (1H, d, 8.5 Hz), 8.08(1H, s), 8.01 (1H, s), 7.60 (1H, d, 8.5 Hz), 7.44 (1H, s), 3.17-3.15(4H, m), 2.83-2.76 (1H, m), 2.47-2.44 (4H, m), 2.04- 1.97 (2H, m), 1.82(2H, t, 9.8 Hz), 1.77 (6H, s), 1.70-1.63 (2H, m)

LCMS: m/z 459, 461 [M+H]⁺

HPLC retention time: 1.63 min (analysis condition S)

Example 411 Compound J26-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

Under the same conditions as the method for synthesizing Compound A2,the title compound was prepared from6-methoxy-3,4-dihydro-1H-naphthalen-2-one and iodomethane.

LCMS: m/z 205 [M+H]⁺

HPLC retention time: 1.54 min (analysis condition S)

Example 412 Compound J3-19-Methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E2-1,the title compound was prepared from Compound J2 and3-hydrazino-benzonitrile.

LCMS: m/z 303 [M+H]⁺

HPLC retention time: 2.73 min (analysis condition S)

Example 413 Compound J3-29-Methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile

Compound J3-2 was obtained as a by-product of the synthesis of CompoundJ3-1.

LCMS: m/z 303 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition S)

Example 414 Compound J49-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound J3-1 and Compound J3-2(mixture).

¹H-NMR (DMSO-d₆) δ: 12.79 (1H, s), 8.33 (1H, d, J=8.2 Hz), 8.02 (1H, s),7.81 (1H, d, J=8.6 Hz), 7.69 (1H, d, J=3.0 Hz), 7.63 (1H, dd, J=8.3, 1.4Hz), 7.28 (1H, dd, J=8.7, 3.0 Hz), 3.87 (3H, s), 1.74 (6H, s).

LCMS: m/z 317 [M+H]⁺

HPLC retention time: 2.25 min (analysis condition S)

Example 415 Compound J59-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound J4.

¹H-NMR (DMSO-d₆) δ: 12.75 (1H, s), 9.77 (1H, s), 8.32 (1H, dd, J=8.2,0.7 Hz), 8.01 (1H, s), 7.68 (1H, d, J=8.6 Hz), 7.62 (1H, dd, J=8.2, 1.4Hz), 7.58 (1H, d, J=2.8 Hz), 7.10 (1H, dd, J=8.6, 2.8 Hz), 1.72 (6H, s).

LCMS: m/z 303 [M+H]⁺

HPLC retention time: 1.75 min (analysis condition S)

Example 416 Compound J6 Trifluoro-methanesulfonic Acid3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl ester

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound J5.

¹H-NMR (DMSO-d₆) δ: 12.95 (1H, s), 8.31 (1H, d, J=8.2 Hz), 8.15 (2H, m),8.05 (1H, s), 7.87 (1H, dd, J=9.0, 2.7 Hz), 7.65 (1H, d, J=8.2 Hz), 1.80(6H, s).

LCMS: m/z 435 [M+H]⁺

HPLC retention time: 2.75 min (analysis condition S)

Example 417 Compound J7-19-Isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound J4 and isopropanol.

LCMS: m/z 345 [M+H]⁺

HPLC retention time: 3.87 min (analysis condition W)

Example 418 Compound J7-2-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound J5.

LCMS: m/z 486 [M+H]⁺

HPLC retention time: 4.15 min (analysis condition W)

Example 419 Compound J7-2-2 6,6-Dimethyl-11-oxo-9-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound J7-2-1.

LCMS: m/z 386 [M+H]⁺

HPLC retention time: 2.48 min (analysis condition W)

Example 420 Compound J7-2-3 6,6-Dimethyl-9-(1-oxetan-3-yl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound J7-2-2 and oxetan-3-one.

LCMS: m/z 442 [M+H]⁺

HPLC retention time: 2.61 min (analysis condition W)

Example 421 Compound J7-36,6-Dimethyl-11-oxo-9-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10,the title compound was prepared from Compound J6 and4-pyrrolidin-1-yl-piperidine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 13.12 (1H, s), 8.32 (1H, d, J=8.1 Hz), 8.01(1H, s), 7.72 (1H, d, J=8.7 Hz), 7.68 (1H, d, J=2.6 Hz), 7.62 (1H, dd,J=8.2, 1.2 Hz), 7.38 (1H, dd, J=9.1, 2.8 Hz), 3.90 (2H, d, J=11.5 Hz),2.76 (2H, t, J=12.2 Hz), 2.14 (2H, d, J=10.9 Hz), 1.91 (4H, br), 1.74(6H, s).

LCMS: m/z 439 [M+H]⁺

HPLC retention time: 1.35 min (analysis condition S)

Example 422 Compound J7-49-(4-Isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10,the title compound was prepared from Compound J6 and1-isopropyl-piperazine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.80 (1H, s), 8.33 (1H, d, J=7.6 Hz), 8.02 (1H, s), 7.66 (3H, m), 7.33 (1H, d, J=8.2 Hz), 3.21 (4H, br), 2.66(5H, m), 1.72 (6H, s), 1.02 (6H, d, J=6.3 Hz).

LCMS: m/z 413 [M+H]⁺

HPLC retention time: 1.38 min (analysis condition S)

Example 423 Compound J7-56,6-Dimethyl-11-oxo-9-pyrrolidin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10,the title compound was prepared from Compound J6 and pyrrolidine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.24 (1H, d, J=8.1 Hz), 7.91 (1H, s), 7.59(1H, d, J=8.6 Hz), 7.45 (1H, d, J=7.9 Hz), 7.30 (1H, d, J=2.6 Hz), 6.85(1H, dd, J=8.6, 2.8 Hz), 3.31 (4H, t, J=6.3 Hz), 1.99 (4H, t, J=6.2 Hz),1.67 (6H, s).

LCMS: m/z 356 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition S)

Example 424 Compound J7-6 6,6-Dimethyl-11-oxo-9-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10,the title compound was prepared from Compound J6 and(S)-2-pyrrolidin-1-yl methyl-pyrrolidine.

LCMS: m/z 439 [M+H]⁺

HPLC retention time: 1.50 min (analysis condition S)

Example 425 Compound J7-76,6-Dimethyl-11-oxo-9-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10,the title compound was prepared from Compound J6 and piperazine.

LCMS: m/z 371 [M+H]⁺

HPLC retention time: 1.31 min (analysis condition S)

Example 426 Compound J7-89-(3-Hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound J6.

LCMS: m/z 369 [M+H]⁺

HPLC retention time: 2.16 min (analysis condition S)

Example 427 Compound J7-99-Ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-2, the title compound was prepared from Compound J7-8.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.31 (1H, d, J=8.1 Hz), 8.23 (1H, d, J=1.8Hz), 8.02 (1H, d, J=1.3 Hz), 7.93 (1H, d, J=8.2 Hz), 7.78 (1H, dd,J=8.2, 1.8 Hz), 7.61 (1H, dd, J=8.1, 1.3 Hz), 4.31 (1H, s), 1.77 (6H,s).

LCMS: m/z 311 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition S)

Example 428 Compound J7-10-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

Under the same conditions as the method for synthesizing CompoundB2-22-1, the title compound was prepared from Compound J6.

LCMS: m/z 468 [M+H]⁺

HPLC retention time: 2.90 min (analysis condition S)

Example 429 Compound J7-10-26,6-Dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound J7-10-1.

LCMS: m/z 368 [M+H]⁺

HPLC retention time: 1.27 min (analysis condition S)

Example 430 Compound J7-11-19-(Piperidin-4-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB2-25-1 and Compound B2-25-2, the title compound was prepared fromCompound J6.

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 1.42 min (analysis condition S)

Example 431 Compound J7-11-29-(1-Isopropyl-piperidin-4-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound J7-11-1 and acetone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.79 (1H, s), 8.33 (1H, d, 7.9 Hz), 8.01(1H, s), 7.98 (1H, d, 1.8 Hz), 7.79 (1H, d, 7.9 Hz), 7.61 (1H, d, 7.9Hz), 7.51-7.49 (1H, m), 2.74 (2H, d, 11.0 Hz), 2.64-2.60 (3H, m), 2.04(2H, t, 10.7 Hz), 1.77 (6H, s), 1.60-1.51 (3H, m), 1.23-1.14 (2H, m),0.94 (6H, d, 6.7 Hz)

LCMS: m/z 426 [M+H]⁺

Example 432 Compound J7-124-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-butyric Acid

9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound J5, 30 mg, 0.099 mmol), 4-bromo-butyric acid methyl ester(24.9 μl, 0.198 mmol) and cesium carbonate (64.5 mg, 0.198 mmol) weredissolved in DMA (0.20 ml) and stirred at room temperature for 4 hr.Water was added to the reaction solution, which was then extracted withdiethyl ether. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The yellow solid obtained afterconcentration under reduced pressure was purified by silica gel columnchromatography (methylene chloride/MeOH) to obtain4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-butyric acid methyl ester as an intermediate.

The intermediate was dissolved in MeOH (0.50 ml), added with aqueoussolution of sodium hydroxide (6 mol/1) and stirred at room temperaturefor 30 min. The reaction solution was added with hydrochloric acid (3mol/1), extracted with diethyl ether. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, white solid was obtained, whichwas then washed with methylene chloride to obtain the title compound(19.0 mg, 70%).

LCMS: m/z 389 [M+H]⁺

HPLC retention time: 2.39 min (analysis condition F)

Example 433 Compound J7-135-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-pentanoic Acid

Under the same conditions as the method for synthesizing Compound J7-12,Compound J5 and 5-bromo-pentanoic acid methyl ester were reacted toobtain the target compound (19.5 mg, 64%).

LCMS: m/z 403 [M+H]⁺

HPLC retention time: 2.49 min (analysis condition F)

Example 434 Compound J7-146-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-hexanoic Acid

Under the same conditions as the method for synthesizing Compound J7-12,Compound J5 and 6-bromo-hexanoic acid ethyl ester were reacted to obtainthe target compound (19.6 mg, 66%).

LCMS: m/z 417 [M+H]⁺

HPLC retention time: 2.61 min (analysis condition F)

Example 435 Compound J7-153-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-ethoxy]-propionic Acid

Under the same conditions as the method for synthesizing Compound A7-1,Compound JJ2 and 3-(2-hydroxy-ethoxy)-propionic acid tert-butyl esterwere reacted to obtain3-[2-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-ethoxy]-propionic acid tert-butyl ester.

The resultant was dissolved in DMA (0.30 ml), added with copper cyanide(25.5 mg, 0.285 mmol), and stirred at 200° C. for 1 hr under irradiationwith microwave. The reaction solution was diluted with ethyl acetate,washed with saturated brine and dried over anhydrous magnesium sulfate.The residues obtained after concentration under reduced pressure weredissolved in methylene chloride (0.75 ml). The solution was added withTFA (250 μl) and stirred at room temperature for 5 min. Thereafter, theresidues obtained from the reaction solution after concentration underreduced pressure were purified by silica gel column chromatography(methylene chloride/MeOH) to obtain the title compound (5.6 mg, 14%).

LCMS: m/z 419 [M+H]⁺

HPLC retention time: 2.31 min (analysis condition F)

Example 436 Compound J7-16 6,6-Dimethyl-11-oxo-9-(pyridin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound J5 andpyridin-4-yl-methanol (pale yellow solid, 6.1 mg, 31%).

LCMS: m/z 394 [M+H]⁺

HPLC retention time: 1.97 min (analysis condition F)

Example 437 Compound J7-17 6,6-Dimethyl-11-oxo-9-(pyridin-3-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound JJ3-1,the title compound was prepared from Compound J5 andpyridin-3-yl-methanol (pale yellow solid, 7.9 mg, 38%).

LCMS: m/z 394 [M+H]⁺

HPLC retention time: 1.99 min (analysis condition F)

Example 438 Compound J8-16,6-Dimethyl-9-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound J7-7 and oxetan-3-one.

LCMS: m/z 427 [M+H]⁺

HPLC retention time: 1.31 min (analysis condition S)

Example 439 Compound J8-29-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound J7-7 and (1-ethoxycyclopropoxy)trimethylsilane.

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 1.39 min (analysis condition S)

Example 440 Compound J8-39-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound J7-10-2.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.81 (1H, s), 8.33 (1H, d, 7.9 Hz), 8.26(1H, d, 2.4 Hz), 8.01 (1H, s), 7.88-7.81 (2H, m), 7.61 (1H, d, 7.9 Hz),6.36 (1H, s), 3.93 (2H, d, 3.0 Hz), 3.45 (2H, t, 5.8 Hz), 2.97 (3H, s),2.73-2.70 (2H, m), 1.78 (6H, s)

LCMS: m/z 446 [M+H]⁺

HPLC retention time: 2.15 min (analysis condition S)

Example 441 Compound J8-49-(1-Isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound J7-10-2 and acetone.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.82 (1H, s), 8.33 (1H, d, 7.9 Hz), 8.22(1H, d, 1.8 Hz), 8.02 (1H, s), 7.84 (1H, d, 8.5 Hz), 7.78 (1H, dd, 8.2,2.1 Hz), 7.62 (1H, d, 7.9 Hz), 6.32 (1H, t, 3.7 Hz), 3.23-3.20 (2H, m),2.83-2.76 (1H, m), 2.72 (2H, t, 5.5 Hz), 2.56-2.54 (2H, m), 1.78 (6H,s), 1.06 (6H, d, 6.7 Hz)

LCMS: m/z 410 [M+H]⁺

HPLC retention time: 1.38 min (analysis condition S)

Example 442 Compound J8-56,6-Dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound J7-10-2 and oxetan-3-one.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.81 (1H, br. s), 8.34 (1H, d, J=8.2 Hz),8.22 (1H, d, J=1.8 Hz), 8.03 (1H, s), 7.76-7.90 (2H, m), 7.64 (1H, dd,J=8.2, 1.8 Hz), 6.25-6.34 (1H, m), 4.60 (2H, dd, J=6.6, 6.0 Hz), 4.52(2H, dd, J=6.6, 6.0 Hz), 3.57 (1H, t, J=6.0 Hz), 3.03 (2H, m), 2.55 (4H,m), 1.77 (6H, s).

LCMS: m/z 424 [M+H]⁺

HPLC retention time: 1.34 min (analysis condition S)

Example 443 Compound J8-69-(1-Cyclopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound J7-10-2 and(1-ethoxycyclopropoxy)trimethylsilane.

LCMS: m/z 408 [M+H]⁺

HPLC retention time: 1.36 min (analysis condition S)

Example 444 Compound J9-14-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-piperidine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound J7-10-1.

LCMS: m/z 414, 470 [M+H]⁺

HPLC retention time: 2.83 min (analysis condition S)

Example 445 Compound J9-26,6-Dimethyl-11-oxo-9-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound J9-1.

LCMS: m/z 370 [M+H]⁺

HPLC retention time: 1.30 min (analysis condition S)

Example 446 Compound J9-39-(1-Isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1,the title compound was prepared from Compound J9-2 and 2-bromopropane.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.83 (1H, s), 8.34 (2H, d, J=8.1 Hz), 8.05(2H, m), 7.82 (1H, d, J=8.1 Hz), 7.61 (2H, m), 3.02 (2H, br), 2.42 (2H,br), 1.76 (6H, s), 1.06 (6H, d, J=6.4 Hz).

LCMS: m/z 412 [M+H]⁺

HPLC retention time: 1.45 min (analysis condition S)

Example 447 Compound J9-46,6-Dimethyl-9-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound J8-5.

LCMS: m/z 426 [M+H]⁺

HPLC retention time: 1.26 min (analysis condition S)

Example 448 Compound J9-59-(1-Cyclopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound J8-6.

LCMS: m/z 410 [M+H]⁺

HPLC retention time: 1.43 min (analysis condition S)

Example 449 Compound JJ13-Bromo-9-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

6-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound J2,2.15 g, 10.5 mmol) and 3-bromophenylhydrazine hydrochloric acid salt(3.11 g, 1.3 eq.) were dissolved in acetic acid (12 mL), and stirred at100° C. for 2.5 hr under nitrogen atmosphere. After cooling, thereaction solution was added with ethyl acetate, washed with water,saturated aqueous solution of sodium hydrogen carbonate, and saturatedbrine, and dried over magnesium sulfate. After the filtration, it wasconcentrated under reduced pressure. The resulting residues weredissolved in THF (30 mL) and water (3 mL), added with DDQ (5.96 g, 2.5eq.) at 0° C., and then stirred at room temperature overnight. Thereaction solution was added with MTBE, washed with 0.5 N aqueoussolution of sodium hydroxide and saturated brine, and dried overmagnesium sulfate. After filtration and the concentration under reducedpressure, the resulting residues were washed with MTBE to obtain thetitle compound (brown solid, 1.80 g, 46%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.4 (1H, s), 8.12 (1H, d, J=8.6 Hz), 7.79(1H, d, J=8.9 Hz), 7.67-7.68 (2H, m), 7.40 (1H, dd, J=1.7, 8.6 Hz), 7.26(1H, dd, J=2.6, 8.9 Hz), 3.86 (3H, s), 1.72 (6H, s),

LCMS: m/z 370 [M+H]⁺

HPLC retention time: 6.45 min (analysis condition H)

Example 450 Compound JJ23-Bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-9-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound JJ1, 1.50 g, 4.05 mmol) and pyridinium chloride (15.2 g, 32.5eq.) were stirred at 160° C. for 12 hr under nitrogen atmosphere. Aftercooling, water and ethyl acetate were added and the resulting suspensionwas filtered. The organic layer was washed with water and saturatedbrine and dried over magnesium sulfate. After filtration and theconcentration under reduced pressure, the resulting residues were washedwith MTBE to obtain the title compound (brown solid, 1.47 g, 100%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.4 (1H, s), 9.71 (1H, s), 8.11 (1H, d,J=8.2 Hz), 7.64-7.68 (2H, m), 7.57 (1H, d, J=3.0 Hz), 7.38 (1H, dd,J=1.7, 8.2 Hz), 7.07 (1H, dd, J=3.0, 8.6 Hz), 1.69 (6H, s),

LCMS: m/z 356 [M+H]⁺

HPLC retention time: 2.52 min (analysis condition F)

Example 451 Compound JJ3-13-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere,3-bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound JJ2, 356 mg, 1.00 mmol) and triphenylphosphine (317 mg, 1.2eq.) were added with THF (3 ml), followed by dropwise addition of((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (148 μl, 1.2 eq.) anddiisopropyl azodicarboxylic acid (252 μl, 1.3 eq.). The mixture was thenstirred at 50° C. for 2 hr. After cooling, the reaction solution wasadded with ethyl acetate, washed with brine and dried over magnesiumsulfate. After filtration and the concentration under reduced pressure,the resulting residues were purified by silica gel column chromatography(ethyl acetate/dichloromethane) to yield the solid, which was thenwashed with dichloromethane to obtain the title compound (white powder,241.6 mg, 51%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.4 (1H, s), 8.12 (1H, d, J=8.2 Hz), 7.79(1H, d, J=8.9 Hz), 7.67-7.69 (2H, m), 7.40 (1H, dd, J=1.8, 8.2 Hz), 7.28(1H, dd, J=3.0, 8.9 Hz), 4.41-4.48 (1H, m), 4.06-4.17 (2H, m), 3.79-3.85(1H, m), 1.72 (3H, s), 1.38 (3H, s), 1.33 (3H, s),

LCMS: m/z 470 [M+H]⁺

HPLC retention time: 3.08 min (analysis condition F)

Example 452 Compound JJ3-23-Bromo-9-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundJJ3-1, 18.7 mg, 0.0398 mmol) was dissolved in methanol (1 mL) and THF(0.3 mL), added with 1 N hydrochloric acid (5 drops) and stirred at 50°C. for 1 hr. After cooling, the reaction solution was concentrated underreduced pressure, and the resulting residues were added withdichloromethane, and the solid was separated by filtration to obtain thetitle compound (yellow powder, 16.8 mg, 98%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.43 (1H, s), 8.12 (1H, d, J=8.6 Hz), 7.78(1H, d, J=8.9 Hz), 7.67-7.70 (2H, m), 7.40 (2H, dd, J=1.8, 8.6 Hz), 7.27(2H, dd, J=2.8, 8.9 Hz), 4.43 (2H, brs), 4.12 (1H, dd, J=9.9, 4.3 Hz),3.96 (1H, dd, J=9.7, 6.1 Hz), 3.85 (1H, dd, J=9.9, 5.6 Hz), 3.48 (2H, d,J=5.6 Hz), 1.72 (6H, s),

LCMS: m/z 430 [M+H]⁺

HPLC retention time: 2.02 min (analysis condition F)

Example 453 Compound JJ4-13-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

To the mixture of 3-bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundJJ3-1, 33.2 mg, 0.0706 mmol) and sodium hydride (60% in oil, 6.4 mg, 2.3eq.), DMA (0.55 mL) and methyl iodide (0.015 mL, 3.4 eq.) were addedunder nitrogen atmosphere at 0° C., and the mixture was stirred at roomtemperature overnight. The reaction solution was added with water andextracted with ethyl acetate. The organic layer was washed with brineand dried over magnesium sulfate. After filtration and the concentrationunder reduced pressure, the resulting solid was washed with MTBE toobtain the title compound (white solid, 31.2 mg, 91%).

LCMS: m/z 484 [M+H]⁺

HPLC retention time: 3.34 min (analysis condition F)

Example 454 Compound JJ4-23-Bromo-9-((R)-2,3-dihydroxy-propoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound JJ3-2,the title compound was prepared from Compound JJ4-1 (yellow solid, 13.3mg, 83%).

LCMS: m/z 444 [M+H]⁺

HPLC retention time: 2.47 min (analysis condition F)

Example 455 Compound JJ5(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-acetic acid

Under the same conditions as the method for synthesizing Compound A7-1,(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-acetic acid methyl ester was prepared from Compound JJ2 andhydroxy-acetic acid methyl ester. The resultant was dissolved in MeOH(0.35 ml), added with aqueous solution of sodium hydroxide (6 mol/1),and stirred at room temperature for 10 min. The reaction solution wasadded with hydrochloric acid (3 mol/1), extracted with diethyl ether anddried over anhydrous magnesium sulfate. After the concentration underreduced pressure, white solid was obtained, which was then washed withmethylene chloride to obtain the title compound (11.2 mg, 48%).

LCMS: m/z 414 [M+H]⁺

HPLC retention time: 2.50 min (analysis condition F)

Example 456 Compound JJ64-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-butyric Acid

3-Bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound JJ2, 20 mg, 0.056 mmol), 4-bromo-butyric acid methyl ester(7.0 μl, 0.056 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) weredissolved in DMA (0.09 ml), and then stirred at room temperature for 1hr. Thereafter, 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol)was added thereto and the mixture was stirred at room temperature for 3hr, followed by further stirring at 45° C. for 30 min. The reactionsolution was added with water, extracted with diethyl ether and driedover anhydrous magnesium sulfate. After the concentration under reducedpressure, the resulting residues were purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain4-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-butyric acid methyl ester. This compound was dissolved in MeOH(0.50 ml), added with aqueous solution of sodium hydroxide (6 mol/1),and then stirred at room temperature for 10 min. The reaction solutionwas added with hydrochloric acid (3 mol/1), extracted with diethylether, and dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain white solid. This white solid was washed withmethylene chloride to obtain the title compound (6.1 mg, 25%).

LCMS: m/z 442 [M+H]⁺

HPLC retention time: 2.65 min (analysis condition F)

Example 457 Compound JJ7-13-Bromo-9-[(4R,5R)-5-(tert-butyl-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A7-1,the title compound (white solid, 111.5 mg, 65%) was prepared fromCompound JJ2 and[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol.

LCMS: m/z 614 [M+H]⁺

HPLC retention time: 4.04 min (analysis condition F)

Example 458 Compound JJ7-23-Bromo-6,6-dimethyl-9-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-9-[(4R,5R)-5-(tert-butyl-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundJJ7-1, 13.7 mg, 0.0223 mmol) was dissolved in THF (0.15 mL) and methanol(0.1 mL), added with 0.5 M sulfuric acid (0.05 mL), and then stirred at60° C. for 3 hr. After cooling, the reaction solution was added withsaturated aqueous solution of sodium hydrogen carbonate and extractedwith ethyl acetate. The organic layer was washed with brine and driedover magnesium sulfate. After filtration and the concentration underreduced pressure, the resulting solid was washed with dichloromethane toobtain the title compound (white solid, 8.4 mg, 82%).

LCMS: m/z 460 [M+H]⁺

HPLC retention time: 2.18 min (analysis condition F)

Example 459 Compound JJ8-19-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA5-2, the title compound (11.1 mg, 50%) was prepared from Compound JJ7-1and[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol.

LCMS: m/z 561 [M+H]⁺

HPLC retention time: 3.84 min (analysis condition F)

Example 460 Compound JJ8-26,6-Dimethyl-11-oxo-9-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound JJ7-2,the title compound was prepared from9-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound JJ8-1) (white solid, 7.8 mg, 97%).

LCMS: m/z 407 [M+H]⁺

HPLC retention time: 1.92 min (analysis condition F)

Example 461 Compound JJ9-19-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundJJ3-1, 49.5 mg, 0.105 mmol) and copper cyanide (90%, 35.3 mg, 3.4 eq.)were added with DMA (0.5 mL), and the mixture was irradiated withmicrowave at 200° C. for 1 hr under nitrogen atmosphere. After cooling,the reaction solution was added with water and extracted with ethylacetate. The insoluble matters were separated off by filtration, and theorganic layer was washed with brine and dried over magnesium sulfate.After filtration and the concentration under reduced pressure, theresulting residues were purified by preparative TLC(methanol/dichloromethane) to obtain the title compound (white solid,8.5 mg, 22%).

LCMS: m/z 377 [M+H]⁺

HPLC retention time: 2.02 min (analysis condition F)

Example 462 Compound JJ9-2 9-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound JJ9-1 (white solid, 24.8 mg, 57%).

LCMS: m/z 417 [M+H]⁺

HPLC retention time: 2.81 min (analysis condition F)

Example 463 Compound JJ9-3 9-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound JJ4-1,the title compound was prepared from9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound JJ9-2) (17.0 mg, 84%).

LCMS: m/z 431 [M+H]⁺

HPLC retention time: 3.00 min (analysis condition F)

Example 464 Compound JJ9-49-((R)-2,3-Dihydroxy-propoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound JJ3-2,the title compound was prepared from9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(JJ9-3) (white solid, 12.1 mg, 90%).

LCMS: m/z 391 [M+H]⁺

HPLC retention time: 2.13 min (analysis condition F)

Example 465 Compound JJ10-19-Benzyloxy-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound JJ2 and benzyl bromide(18.2 mg, 61%).

LCMS: m/z 446 [M+H]⁺

HPLC retention time: 2.68 min (analysis condition D)

Example 466 Compound JJ10-25-Benzyl-9-benzyloxy-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

The title compound was obtained as a by-product of the synthesis ofCompound JJ10-1 (5.3 mg, 21%).

LCMS: m/z 536 [M+H]⁺

HPLC retention time: 3.17 min (analysis condition D)

Example 467 Compound JJ10-33-Bromo-9-(4-methoxy-benzyloxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared by reacting Compound JJ2 and(4-methoxyphenyl)-methanol (7.5 mg, 28%).

LCMS: m/z 476 [M+H]⁺

HPLC retention time: 2.70 min (analysis condition D)

Example 468 Compound K22-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionitrile

To the THF suspension of potassium tert-butoxide (15.35 g, 3 eq.),(3-bromo-4-methoxyphenyl)acetonitrile (Compound K1, 10 g, 0.044 mmol)was added, and then stirred at 0° C. for 1 hr. Then, iodomethane (8.26ml, 3 eq.) was added and the mixture was stirred at room temperature for1 hr. To the reaction solution, saturated aqueous solution of ammoniumchloride and water were added followed by extraction with ethyl acetate.The organic layer was washed with brine and dried over sodium sulfate.The drying agent was removed by filtration and the residues obtainedafter concentration under reduced pressure were purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain the titlecompound (colorless oily substance, 11.24 g, 100%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 7.69 (1H, d, J=2.5 Hz), 7.50 (1H, dd,J=8.6, 2.5 Hz), 7.16 (1H, d, J=8.6 Hz), 3.86 (3H, s), 1.67 (6H, s).

HPLC retention time: 2.30 min (analysis condition S)

Example 469 Compound K34-(3-Bromo-4-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl ester

To the THF suspension of zinc (5.72 g, 2 eq.), methanesulfonic acid(25.6 μl, 0.01 eq.) was added, and then stirred at 80° C. for 10 min.Then, the THF solution of2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionitrile (10 g, 39.35 mmol)was added, followed by addition of bromoethyl acetate (11.07 ml, 1.6eq.) over 1 hr. The mixture was further stirred for 30 min. To thereaction solution, 4 M hydrochloric acid was added, and stirred at roomtemperature overnight. After extraction with ethyl acetate, the organiclayer was washed with brine and dried over sodium sulfate. The dryingagent was removed by filtration and the residues obtained afterconcentration under reduced pressure were purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound(orange oily substance, 9.74 g, 72%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.46 (1H, d, J=2.5 Hz), 7.16 (1H, dd, J=8.6,2.5 Hz), 6.89 (1H, d, J=8.6 Hz), 4.17-4.08 (2H, m), 3.90 (3H, s), 3.26(2H, s), 1.49 (6H, s), 1.23 (3H, t, J=7.2 Hz).

LCMS: m/z 343, 345 [M+H]⁺

HPLC retention time: 2.64 min (analysis condition S)

Example 470 Compound K44-(3-Bromo-4-methoxy-phenyl)-2-(4-cyano-2-nitro-phenyl)-4-methyl-3-oxo-pentanoicAcid Ethyl Ester

4-(3-Bromo-4-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl ester(Compound K3, 10.3 g, 30.01 mmol) was dissolved in DMF (80 mL), addedwith cesium carbonate (24.4 g, 2.5 eq.) and4-chloro-3-nitro-benzonitrile (7.12 g, 1.3 eq.), and then stirred at 45°C. for 4 hr. The reaction solution was added to 1 N aqueous solution ofhydrochloric acid, and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over sodium sulfate. Thedrying agent was removed by filtration, and after concentration underreduced pressure the title compound was obtained as a crude product(yellow oily substance).

LCMS: m/z 489, 491 [M+H]⁺

HPLC retention time: 2.85, 3.20 min (analysis condition S)

Example 471 Compound K52-[1-(3-Bromo-4-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carboxylicAcid Ethyl Ester

4-(3-Bromo-4-methoxy-phenyl)-2-(4-cyano-2-nitro-phenyl)-4-methyl-3-oxo-pentanoicacid ethyl ester (Compound K4), which had been obtained from the above,was dissolved in THF (140 mL) and water (70 mL), added with Na₂S₂O₄(26.13 g, 5.0 eq.) and stirred at 50° C. overnight. The reactionsolution was added to saturated brine and extracted with ethyl acetate.The organic layer was washed with 1 M aqueous solution of potassiumcarbonate and saturated brine in order, and dried over sodium sulfate.The drying agent was removed by filtration and the residues obtainedafter concentration under reduced pressure were purified bycrystallization in MeCN (80 ml) to obtain the title compound (yellowsolid, 8.20 g, 62%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.15 (1H, s), 8.07 (1H, d, J=8.4 Hz), 7.94(1H, s), 7.51 (1H, dd, J=8.5, 1.2 Hz), 7.33 (1H, d, J=2.1 Hz), 7.03 (1H,dd, J=8.7, 2.4 Hz), 6.96 (1H, d, J=8.4 Hz), 3.97 (2H, q, J=7.3 Hz), 3.78(3H, s), 1.80 (6H, s), 1.09 (3H, t, J=7.2 Hz).

LCMS: m/z 441, 443 [M+H]⁺

HPLC retention time: 2.85 min (analysis condition S)

Example 472 Compound K68-Bromo-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Phosphorus pentoxide-methanesulfonic acid (12 mL) was added with2-[1-(3-bromo-4-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carboxylicacid ethyl ester (Compound K5, 1.0 g, 2.27 mmol), and the mixture wasstirred at room temperature for 20 min. The reaction solution wasdiluted with MeCN (20 mL), poured into water (20 mL), and theprecipitated solid was filtered to obtain the title compound (yellowsolid, 763 mg, 85%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.84 (1H, s), 8.32 (1H, d, J=8.1 Hz), 8.15(1H, s), 8.03 (1H, s), 7.77 (1H, s), 7.64 (1H, dd, J=8.2, 1.4 Hz), 3.97(3H, s), 1.75 (6H, s).

LCMS: m/z 395, 397 [M+H]⁺

HPLC retention time: 2.58 min (analysis condition S)

Example 473 Compound K7-19-Methoxy-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound K6 and4-pyrrolidin-1-yl-piperidine.

LCMS: m/z 469 [M+H]⁺

HPLC retention time: 1.37 min (analysis condition S)

Example 474 Compound K7-29-Methoxy-6,6-dimethyl-8-(4-morpholin-1-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound K6 and4-piperidin-4-yl-morpholine.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.70 (1H, s), 8.31 (1H, d, J=8.2 Hz), 7.99(1H, s), 7.63 (1H, s), 7.60 (1H, dd, J=8.2, 1.2 Hz), 7.16 (1H, s), 3.89(3H, s), 3.64 (2H, brd), 2.72 (2H, brd), 1.91 (2H, brd), 1.73 (6H, s),1.57 (2H, brd).

LCMS: m/z 485 [M+H]⁺

HPLC retention time: 1.33 min (analysis condition S)

Example 475 Compound K7-39-Methoxy-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the target compound was prepared from Compound K6 and piperazine.

LCMS: m/z 401 [M+H]⁺

HPLC retention time: 1.31 min (analysis condition S)

Example 476 Compound K7-49-Methoxy-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound K6 and morpholine.

LCMS: m/z 402 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition S)

Example 477 Compound K88-(4-Cyclobutyl-piperazin-1-yl)-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound K7-3 and cyclobutanone.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.70 (1H, br. s), 8.31 (1H, d, J=8.2 Hz),8.00 (1H, s), 7.64 (1H, s), 7.61 (1H, dd, J=8.1, 1.3 Hz), 7.16 (1H, s),3.88 (3H, s), 3.60 (1H, t, J=6.2 Hz), 3.10-3.25 (4H, m), 2.77 (1H, t,J=7.1 Hz), 2.35-2.51 (4H, m), 1.74 (6H, s), 1.58-2.08 (6H, m).

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 1.45 min (analysis condition S)

Example 478 Compound K9-19-Hydroxy-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound K7-1.

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 1.22 min (analysis condition S)

Example 479 Compound K9-29-Hydroxy-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound K7-2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.65 (1H, s), 9.61 (1H, s), 8.30 (1H, d,J=8.2 Hz), 7.98 (1H, s), 7.59-7.56 (2H, m), 7.10 (1H, s), 3.71 (2H, brd,J=11.2 Hz), 3.60 (4H, m), 2.66 (2H, m), 1.88 (2H, brd, J=9.7 Hz), 1.71(6H, s), 1.57 (2H, brd).

LCMS: m/z 471 [M+H]⁺

HPLC retention time: 1.20 min (analysis condition S)

Example 480 Compound K9-38-(4-Cyclobutyl-piperazin-1-yl)-9-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound K8.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.66 (1H, br. s), 9.67 (1H, s), 8.31 (1H,d, J=8.2 Hz), 7.98 (1H, s), 7.56-7.60 (2H, m), 7.09 (1H, s), 3.10-3.24(4H, m), 2.77 (1H, t, J=7.5 Hz), 2.37-2.49 (4H, m), 1.52-2.07 (6H, m),1.72 (6H, s).

LCMS: m/z 441 [M+H]⁺

HPLC retention time: 1.31 min (analysis condition S)

Example 481 Compound K9-49-Hydroxy-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound K7-4.

LCMS: m/z 388 [M+H]⁺

HPLC retention time: 1.67 min (analysis condition S)

Example 482 Compound K10-19-Isopropoxy-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound K9-2 and 2-bromopropane.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.68 (1H, s), 8.30 (1H, d, J=8.1 Hz), 7.99(1H, s), 7.60 (2H, m), 7.14 (1H, s), 4.72-4.63 (2H, m), 3.71 (2H, brd,J=10.7 Hz), 3.59 (6H, m), 2.68 (2H, t, J=12.9 Hz), 2.27 (2H, brd), 1.90(2H, brd), 1.73 (6H, s), 1.56 (2H, br), 1.34 (6H, d, J=5.9 Hz).

LCMS: m/z 513 [M+H]⁺

HPLC retention time: 1.48 min (analysis condition S)

Example 483 Compound K10-28-(4-Cyclobutyl-piperazin-1-yl)-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound K9-3 and 2-iodopropane.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.29 (1H, d, J=8.1 Hz), 7.98 (1H, s),7.56-7.63 (2H, m), 7.14 (1H, s), 4.62-4.74 (1H, m), 3.10-3.26 (4H, m),2.69-2.85 (1H, m), 2.35-2.48 (4H, m), 1.57-2.08 (6H, m), 1.73 (6H, s),1.32 (6H, d, J=6.1 Hz).

LCMS: m/z 483 [M+H]⁺

HPLC retention time: 1.65 min (analysis condition S)

Example 484 Compound K10-39-(2-Methoxy-ethoxy)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound K9-4 and1-bromo-2-methoxyethane.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.67 (1H, s), 8.30 (1H, d, 7.9 Hz), 7.98(1H, s), 7.64 (1, s), 7.58 (1H, d, 7.9 Hz), 7.16 (1H, s), 4.18-4.22 (2H,m), 3.72-3.80 (6H, m), 3.35 (3H, s), 3.18-3.24 (4H, s), 1.74 (1H, s)

LCMS: m/z 446 [M+H]⁺

HPLC retention time: 3.23 min (analysis condition W)

Example 485 Compound K10-49-[2-(2-Methoxy-ethoxy)-ethoxy]-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound K9-4 and1-bromo-2-(2-methoxyethoxy)ethane.

LCMS: m/z 490 [M+H]⁺

HPLC retention time: 3.16 min (analysis condition W)

Example 486 Compound K10-56,6-Dimethyl-8-morpholin-1-yl-11-oxo-9-[(S)-(tetrahydro-furan-3-yl)oxy]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound K9-4 and3-mesyloxytetrahydrofurane.

LCMS: m/z 458 [M+H]⁺

HPLC retention time: 3.20 min (analysis condition W)

Example 487 Compound K10-69-Isopropoxy-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound K9-4 and 2-bromopropane.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.70 (1H, br. s), 8.32-8.29 (1H, d, 8.08Hz), 8.00 (1H, s), 7.63 (1H, s), 7.62-7.59 (1H, d, 8.08 Hz), 7.16 (1H,s), 4.75-4.66 (1H, m), 3.77 (4H, m) 3.19 (4H, m), 1.74 (6H, s), 1.35(3H, s), 1.33 (3H, s)

LCMS: m/z 430 [M+H]⁺

Example 488 Compound K10-79-(2-Hydroxy-ethoxy)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound K9-4 and 2-bromoethanol.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.71 (1H, br. s), 8.33-8.30 (1H, d, 8.08Hz), 8.00 (1H, s), 7.63 (1H, s), 7.62-7.59 (1H, d, 8.08 Hz), 7.16 (1H,s), 4.13-4.09 (2H, t, 4.61 Hz), 3.81-3.78 (2H, t, 4.61 Hz), 3.78 (4H, m)3.23 (4H, m), 1.75 (6H, s)

LCMS: m/z 432 [M+H]⁺

Example 489 Compound L2-1 (4-Isopropoxy-3-methoxy-phenyl)-ethyl AcetateEster

(4-Hydroxy-3-methoxy-phenyl)-ethyl acetate ester (Compound L1-1, 3.0 g,14.27 mmol) was dissolved in DMF (70 mL), added with 2-iodopropane (2.9mL, 2.0 eq.) and potassium carbonate (3.94 g, 2.0 eq.), and stirred at80° C. overnight. The reaction solution was added to water and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over sodium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/hexane) to obtain the target compound (yellow oily substance,2.61 g, 73%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 6.88 (2H, m), 6.74 (1H, dd, J=8.1, 2.1 Hz),4.52-4.43 (1H, m), 4.07 (2H, q, J=7.1 Hz), 3.72 (3H, s), 3.56 (2H, s),1.23 (6H, d, J=6.1 Hz), 1.18 (3H, t, J=7.1 Hz).

LCMS: m/z 253 [M+H]⁺

HPLC retention time: 2.18 min (analysis condition S)

Example 490 Compound L2-2 (4-Isopropoxy-3-methoxy-phenyl)-acetic AcidIsopropyl Ester

(4-Hydroxy-3-methoxy-phenyl)-acetic acid (Compound L1-2, 1.5 g, 8.23mmol) was dissolved in DMF (30 mL), added with 2-iodopropane (3.3 mL,4.0 eq.) and potassium carbonate (4.55 g, 4.0 eq.), and stirred at 80°C. overnight. The reaction solution was added to water and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over sodium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/hexane) to obtain the target compound (yellow oily substance,1.21 g, 55%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 6.87 (2H, s+d), 6.73 (1H, dd, J=8.1, 2.1Hz), 4.94-4.84 (1H, m), 4.52-4.43 (1H, m), 3.72 (3H, s), 3.52 (2H, s),1.23 (6H, d, J=6.1 Hz), 1.18 (6H, d, J=6.1 Hz).

LCMS: m/z 267 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition S)

Example 491 Compound L3-12-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic Acid Ethyl Ester

Under the same conditions as the method for synthesizing Compound K2,the title compound was prepared from Compound L2-1.

¹H-NMR (270 MHz, DMSO-d₆) δ: 6.90-6.76 (3H, m), 4.53-4.44 (1H, m), 4.06(2H, q, J=7.1 Hz), 3.73 (3H, s), 1.47 (6H, s), 1.23 (6H, d, J=6.1 Hz),1.12 (3H, t, J=7.0 Hz).

LCMS: m/z 281 [M+H]⁺

HPLC retention time: 2.57 min (analysis condition S)

Example 492 Compound L3-22-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic Acid IsopropylEster

Under the same conditions as the method for synthesizing Compound K2,the title compound was prepared from Compound L2-2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 6.88 (1H, d, J=8.2 Hz), 6.79 (2H, m), 4.94-4.84 (1H, m), 4.53-4.44 (1H, m), 3.72 (3H, s), 1.45 (6H, s), 1.23(6H, d, J=6.1 Hz), 1.12 (6H, d, J=6.3 Hz).

LCMS: m/z 295 [M+H]⁺

HPLC retention time: 2.75 min (analysis condition S)

Example 493 Compound L42-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic Acid

2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid ethyl ester(Compound L3-1, 1.45 g, 5.17 mmol) was dissolved in THF (13 mL) and EtOH(13 mL), added with 1 N aqueous solution of sodium hydroxide (10.3 mL,2.0 eq.), and stirred at 80° C. overnight. The reaction solution wasadded to water and extracted with ethyl acetate. The aqueous layer wasacidified by using 1 N aqueous solution of hydrochloric acid, extractedwith ethyl acetate, washed with saturated brine and dried over sodiumsulfate. The drying agent was removed by filtration and the residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetarget compound (white solid, 1.10 g, 84%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.26 (1H, s), 6.90-6.80 (3H, m), 4.49 (1H,m), 3.73 (3H, s), 1.45 (6H, s), 1.23 (6H, d, J=6.1 Hz).

LCMS: m/z 253 [M+H]⁺

HPLC retention time: 1.83 min (analysis condition S)

Example 494 Compound L54-(4-Isopropoxy-3-methoxy-phenyl)-4-methyl-3-oxo-pentanoic Acid EthylEster

2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid (Compound L4,1.4 g, 5.55 mmol) was added with thionyl chloride (10 mL), and thenstirred at room temperature for 5 hr. According to the concentrationunder reduced pressure, unreacted thionyl chloride was removed to obtaincorresponding acid chloride.

To MeCN (40 mL), malonic acid monoethyl ester potassium salt (1.98 g,2.1 eq.), triethylamine (2.47 mL, 3.2 eq.), and magnesium chloride (1.32g, 2.5 eq.) were added and the mixture was stirred at room temperaturefor 2 hr. To the reaction solution, MeCN (15 mL) solution of the acidchloride prepared from the above was added dropwise. Upon the completionof the dropwise addition, the mixture was further stirred at roomtemperature for overnight. MeCN was removed by distillation andconcentrated under reduced pressure, and the resulting residues wereadded with 1 N aqueous solution of hydrochloric acid, extracted withtoluene, washed with saturated brine, and dried over sodium sulfate. Thedrying agent was removed by filtration and the residues obtained afterconcentration under reduced pressure were purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the target compound(yellow oily substance, 1.45 g, 81%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 6.94 (1H, d, J=8.2 Hz), 6.76 (2H, m),4.56-4.47 (1H, m), 4.00 (2H, q, J=7.1 Hz), 3.74 (3H, s), 3.38 (2H, s),1.41 (6H, s), 1.24 (6H, d, J=6.1 Hz), 1.12 (3H, t, J=7.3 Hz).

LCMS: m/z 323 [M+H]⁺

HPLC retention time: 2.45, 3.03 min (analysis condition S)

Example 495 Compound L62-(4-Cyano-2-nitro-phenyl)-4-(4-isopropoxy-3-methoxy-phenyl)-4-methyl-3-oxo-pentanoicAcid Ethyl Ester

Under the same conditions as the method for synthesizing Compound K4,the title compound was prepared from Compound L5.

¹H-NMR (270 MHz, DMSO-d₆) δ: 8.35 (1H, d, J=1.8 Hz), 8.14 (1H, dd,J=8.2, 1.9 Hz), 7.67 (1H, d, J=8.2 Hz), 6.68 (1H, d, J=8.4 Hz), 6.59(1H, dd, J=8.4, 2.0 Hz), 6.45 (1H, d, J=2.1 Hz), 5.44 (1H, s), 4.43 (1H,m), 4.09 (2H, q, J=7.1 Hz), 3.53 (3H, s), 1.59 (3H, s), 1.35 (3H, s),1.24 (6H, dx2), 1.13 (3H, t, J=7.1 Hz).

LCMS: m/z 469 [M+H]⁺

HPLC retention time: 2.85, 3.10 min (analysis condition S)

Example 496 Compound L76-Cyano-2-[1-(4-isopropoxy-3-methoxy-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylicAcid Ethyl Ester

Under the same conditions as the method for synthesizing Compound K5,the title compound was prepared from Compound L6.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.04 (1H, s), 8.05 (1H, d, J=8.4 Hz), 7.93(1H, s), 7.49 (1H, dd, J=8.4, 1.5 Hz), 6.79 (2H, m), 6.54 (1H, dd,J=8.3, 1.9 Hz), 4.43 (1H, t, J=6.1 Hz), 3.94 (2H, q, J=7.0 Hz), 3.65(3H, s), 1.81 (6H, s), 1.21 (6H, d, J=5.9 Hz), 1.05 (3H, t, J=7.1 Hz).

LCMS: m/z 421 [M+H]⁺

HPLC retention time: 2.82 min (analysis condition S)

Example 497 Compound L8-19-Hydroxy-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6-Cyano-2-[1-(4-isopropoxy-3-methoxy-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylicacid ethyl ester (Compound L7, 1.25 g, 2.97 mmol) was dissolved in MeCN(18 mL), added with methanesulfonic acid (3.75 mL), and then stirred at50° C. for 8 hr. Hexane was added to the reaction solution, and theprecipitated solid was filtered to obtain the title compound (yellowsolid, 185 mg, 19%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.67 (1H, s), 8.30 (1H, d, J=8.2 Hz), 7.99(1H, s), 7.59 (2H, m), 7.28 (1H, s), 3.93 (3H, s), 1.75 (6H, s).

LCMS: m/z 333 [M+H]⁺

HPLC retention time: 1.73 min (analysis condition S)

Example 498 Compound L8-29-Isopropoxy-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the filtrate obtained from the synthesis of Compound L8-1, water wasadded and the extraction was carried out with ethyl acetate. Theresultant was washed with saturated brine and dried over sodium sulfate.The drying agent was removed by filtration and the concentration wasperformed under reduced pressure to obtain the target compound (redamorphous, 830 mg, 75%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.72 (1H, s), 8.31 (1H, d, J=8.4 Hz), 8.01(1H, d, J=0.7 Hz), 7.66 (1H, s), 7.61 (1H, dd, J=8.2, 1.4 Hz), 7.33 (1H,s), 4.65 (1H, m), 3.93 (3H, s), 1.77 (6H, s), 1.32 (6H, d, J=6.1 Hz).

LCMS: m/z 375 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition S)

Example 499 Compound L98-Hydroxy-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound L8-2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 12.69 (1H, s), 9.69 (1H, s), 8.30 (1H, d,J=8.1 Hz), 7.99 (1H, s), 7.65 (1H, s), 7.60 (1H, dd, J=8.2, 1.2 Hz),7.17 (1H, s), 4.64 (1H, m), 1.69 (6H, s), 1.32 (6H, d, J=6.1 Hz).

LCMS: m/z 361 [M+H]⁺

HPLC retention time: 2.20 min (analysis condition S)

Example 500 Compound L10-18-(1-Cyclobutyl-piperidin-4-yloxy)-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound L9 and1-cyclobutylpiperidin-4-ol.

¹H-NMR (270 MHz, CDCl₃) δ: 9.31 (1H, br. s), 8.54-8.50 (1H, d, 8.08 Hz),7.90 (1H, s), 7.77 (1H, s), 7.59-7.55 (1H, m), 7.09 (1H, s), 4.70-4.61(1H, m), 4.52-4.43 (1H, m), 2.79-2.73 (1H, m), 2.70-2.60 (2H, m),2.25-2.16 (2H, m), 2.09-1.99 (4H, m), 1.98-1.88 (4H, m), 1.77 (6H, s),1.72-1.58 (2H, m), 1.39 (3H, s), 1.37 (3H, s)

LCMS: m/z 498 [M+H]⁺

Example 501 Compound L10-2 8-((R)-1-Cyclobutyl-pyrrolidin-3-yloxy)-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound L9 and(S)-1-cyclobutylpyrrolidin-3-ol.

¹H-NMR (270 MHz, CDCl₃) δ: 10.63 (1H, br. s), 8.51-8.48 (1H, d, 8.08Hz), 7.89 (1H, s), 7.85 (1H, s), 7.55-7.51 (1H, m), 6.99 (1H, s),5.03-4.97 (1H, m), 4.71-4.62 (1H, m), 3.07-292 (2H, m), 2.84-2.73 (2H,m), 2.64-2.53 (1H, m), 2.36-2.23 (2H, m), 2.10-1.97 (2H, m), 1.83-1.67(2H, m), 1.78 (6H, s), 1.53-1.46 (2H, m), 1.39 (3H, s), 1.37 (3H, s)

LCMS: m/z 484 [M+H]⁺

Example 502 Compound M17-Methoxy-3,4-dihydro-2H-spiro[cyclopentane-1,1′-naphthalen]-2-one

To the THF (300 ml) solution of7-methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 0.5 g, 2.84mmol), sodium hydride (36.4 mg, 2.2 eq.) was added at 0° C. Afterstirring for 20 min, 1,4-dibromobutane (0.74 ml, 1.2 eq.) was addeddropwise thereto, and the mixture was stirred at 80° C. for 4 hr. To thereaction solution, saturated aqueous solution of ammonium chloride wasadded followed by extraction with ethyl acetate. The organic layer waswashed with saturated aqueous solution of ammonium chloride and driedover magnesium sulfate. The drying agent was removed by filtration andthe residues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (yellow solid, 0.31 g, 47%).

¹H-NMR (CDCl₃, 300 MHz): 1.79-1.92 (6H, m), 2.42-2.27 (m, 2H), 3.03 (t,2H, J=6.5 Hz), 3.81 (t, 2H, J=6.5 Hz), 3.81 (s, 3H), 6.73 (dd, 1H, J=2.7Hz, 8.0 Hz), 6.83 (d, 1H, J=2.7 Hz), 7.09 (d, 1H, J=8.0 Hz)

LCMS: m/z 231 [M+H]⁺

Example 503 Compound M23-Bromo-8-methoxy-5,11-dihydrospiro[benzo[b]carbazole-6,1′-cyclopentane]

Under the same conditions as the method for synthesizing Compound A3-1,the title compound was prepared from Compound M1 and(3-bromo-phenyl)-hydrazine.

LCMS: m/z 380, 382 [M+H]⁺

HPLC retention time: 2.90 min (analysis condition Y)

Example 504 Compound M33-Bromo-8-methoxyspiro[benzo[b]carbazole-6,1′-cyclopentan]-11(5H)-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound M2.

¹H-NMR (CDCl₃, 300 MHz) δ: 2.11-2.51 (8H, m), 3.91 (s, 3H), 6.98 (dd,1H, J=2.3 Hz, 8.8 Hz), 7.01 (d, 1H, J=2.3 Hz), 7.41 (dd, 1H, J=1.5 Hz,8.4 Hz), 7.57 (d, 1H, J=1.5 Hz), 8.30 (d, 1H, J=8.4 Hz), 8.35 (d, 1H,J=8.8 Hz), 8.69 (s, 1H)

LCMS: m/z 396, 398 [M+H]⁺

Example 505 Compound M48-Methoxy-11-oxo-5,11-dihydrospiro[benzo[b]carbazole-6,1′-cyclopentane]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A5-2,the title compound was prepared from Compound M3.

¹H-NMR (DMSO-d₆, 300 MHz) δ: 2.14-2.37 (m, 8H), 3.90 (s, 3H), 7.05-7.10(m, 2H), 7.60 (dd, 1H, J=1.5 Hz, 8.4 Hz), 7.95 (s, 1H), 8.13 (d, 1H,J=9.5 Hz), 8.30 (d, 1H, J=8.4 Hz), 12.24 (s, 1H)

LCMS: m/z 343 [M+H]⁺

Example 506 Compound M58-Hydroxy-11-oxo-5,11-dihydrospiro[benzo[b]carbazole-6,1′-cyclopentane]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound M4.

¹H-NMR (DMSO-d₆, 300 MHz) δ: 2.06-2.39 (m, 8H), 6.87 (dd, 1H, J=1.9 Hz,8.8 Hz), 6.90 (d, 1H, J=1.9 Hz), 7.57 (dd, 1H, J=1.1 Hz, 8.0 Hz), 7.95(s, 1H), 8.02 (d, 1H, J=8.8 Hz), 8.30 (d, 1H, J=8.0 Hz), 10.29 (s, 1H),12.25 (s, 1H)

LCMS: m/z 329 [M+H]⁺

Example 507 Compound M6-1(S)-8-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-11-oxo-5,11-dihydrospiro[benzo[b]carbazole-6,1′-cyclopentane]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared as a crude product from Compound M5 andtoluene-4-sulfonic acid(R)-2,2-dimethyl-[1,3]dioxolan-4-yl methyl ester.

Example 508 Compound M6-2(R)-8-(2,3-Dihydroxypropoxy)-11-oxo-5,11-dihydrospiro[benzo[b]carbazole-6,1′-cyclopentane]-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound M6-1.

LCMS: m/z 403 [M+H]⁺

HPLC retention time: 2.88 min (analysis condition U)

Example 509 Compound N17-Methoxy-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[naphthalene-1,4′-pyran]-2-one

To the THF (300 ml) solution of7-methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 20 g, 0.11 mol),sodium hydride (9.9 g, 3.7 eq.) was added at 0° C. After stirring for 10min, 1-bromo-2-(2-bromo-ethoxy)-ethane (19 ml, 12 eq.) was addeddropwise thereto, and the mixture was stirred at 80° C. for 3 hr. To thereaction solution, saturated aqueous solution of ammonium chloride wasadded and the extraction was carried out twice with ethyl acetate. Theorganic layer was dried over magnesium sulfate. The drying agent wasremoved by filtration and the residues obtained after concentrationunder reduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (white solid, 13 g,51%).

¹H-NMR (300 MHz, CDCl₃) δ: 2.07 (4H, m), 2.70 (t, 2H, 6.8 Hz), 3.12 (t,2H, 6.8 Hz), 3.81 (s, 3H), 3.89 (m, 4H), 6.75 (dd, 1H, 2.6 Hz, 8.3 Hz),6.9 (d, 1H, 2.6 Hz), 7.0 (d, 1H, 8.3 Hz)

LCMS: m/z 247 [M+H]⁺

Example 510 Compound N2-1, Compound N2-23-Bromo-8-methoxy-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]1-Bromo-8-methoxy-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]

Under the same conditions as the method for synthesizing Compound A3-1,the title compound was prepared as a mixture from Compound N1.

Example 511 Compound N33-Bromo-8-methoxy-2′,3′,5′,6′-tetrahydrospiro[benzo[b]carbazole-6,4′-pyran]-11(5H)-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound N2-1.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.9 (2H, m), 2.4 (m, 2H), 3.9 (s, 3H), 4.0(m, 2H), 4.2 (m, 2H), 7.1 (dd, 1H, 2.2 Hz, 8.7 Hz), 7.3 (m, 2H), 7.8 (d,1H, 2.2 Hz), 8.1 (d, 2H, 8.7 Hz), 11.8 (s, 1H)

LCMS: m/z 413(M+1)⁺

Example 512 Compound N48-Methoxy-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A5-2,the title compound was prepared from Compound N3.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.9 (m, 2H), 2.4 (m, 2H), 3.9 (s, 3H), 4.0(m, 2H), 4.1 (m, 2H), 7.1 (dd, 1H, 2.2 Hz, 8.7 Hz), 7.4 (d, 1H, 2.2 Hz),7.6 (dd, 1H, 1.5 Hz, 8.3 Hz), 8.0 (s, 1H), 8.1 (d, 1H, 8.7 Hz), 8.3 (d,1H, 8.3 Hz), 12.2 (s, 1H)

LCMS: m/z 359 [M+H]⁺

HPLC retention time: 2.80 min (analysis condition U)

Example 513 Compound N58-Hydroxy-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound N4.

¹H-NMR (300 MHz, DMSO-d₆) d ppm 2.0 (m, 2H), 2.3 (m, 2H), 4.0 (m, 2H),4.1 (m, 2H), 6.9 (dd, 1H, 1.9 Hz, 8.3 Hz), 7.3 (d, 1H, 1.9 Hz), 7.6 (dd,1H, 1.5 Hz, 8.3 Hz), 8.0 (s, 1H), 8.1 (d, 1H, 8.3 Hz), 8.3 (d, 1H, 8.3Hz), 10.3 (s, 1H), 12.2 (s, 1H)

LCMS: m/z 345 [M+H]⁺

HPLC retention time: 2.37 min (analysis condition U)

Example 514 Compound N6-1-1 (S)-8-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound N6-2 and(S)-2,2-dimethyl-4-p-tolyloxymethyl-[1,3]dioxolane.

LCMS: m/z 459 [M+H]⁺

HPLC retention time: 2.93 min (analysis condition Y)

Example 515 Compound N6-1-2(R)-8-(2,3-Dihydroxypropoxy)-1-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound N6-1-1.

LCMS: m/z 419 [M+H]⁺

HPLC retention time: 1.52 min (analysis condition S)

Example 516 Compound N6-211-Oxo-8-(piperidin-4-yloxy)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1and Compound A8-1, the title compound was prepared from Compound N5.

LCMS: m/z 428 [M+H]⁺

HPLC retention time: 1.38 min (analysis condition S)

Example 517 Compound N6-38-(3-Morpholinoethoxy)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17,the title compound was prepared from Compound N5.

LCMS: m/z 458 [M+H]⁺

HPLC retention time: 1.33 min (analysis condition S)

Example 518 Compound N6-48-(3-Morpholinopropoxy)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17,the title compound was prepared from Compound N5.

LCMS: m/z 472 [M+H]⁺

HPLC retention time: 1.41 min (analysis condition S)

Example 519 Compound N6-53-Cyano-8-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonicAcid Dimethylamide

Under the same conditions as the method for synthesizing Compound A8-17,the title compound was prepared from Compound N5.

LCMS: m/z 506 [M+H]⁺

HPLC retention time: 1.53 min (analysis condition S)

Example 520 Compound N6-68-(1-Ethylpiperidin-4-yloxy)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound N6-2.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.02 (3H, t, 7.25 Hz), 1.18 (2H, m), 1.71(2H, m), 1.97 (4H, m), 2.27 (2H, m), 2.38 (3H, m), 2.71 (2H, m), 4.03(2H, m), 4.21 (2H, m), 4.66 (1H, s), 7.13 (1H, dd, 8.77 Hz, 1.91 Hz),7.39 (1H, bs, 1.91 Hz), 7.60 (1H, d, 8.40 Hz), 8.07 (1H, s), 8.15 (1H,d, 8.40 Hz), 8.37 (1H, d, 8.01 Hz), 12.2 (1 H, s).

LCMS: m/z 456 [M+H]⁺

HPLC retention time: 1.48 min (analysis condition S)

Example 521 Compound N7 Trifluoromethanesulfonic Acid3-cyano-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-8-yl

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound N5.

LCMS: m/z 477 [M+H]⁺

HPLC retention time: 3.58 min (analysis condition Y)

Example 522 Compound N8-111-Oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound N7 and4-pyrrolidin-1-yl-piperidine.

LCMS: m/z 481 [M+H]⁺

HPLC retention time: 1.75 min (analysis condition U)

Example 523 Compound N8-28-(4-Morpholinopiperidin-1-yl)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound N7 and4-piperidin-4-yl-morpholine.

LCMS: m/z 497 [M+H]⁺

HPLC retention time: 1.70 min (analysis condition U)

Example 524 Compound O16-Bromo-7-methoxy-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[naphthalene-1,4′-pyran]-2-one

Under the same conditions as the method for synthesizing Compound E-1,the title compound was prepared from Compound N1.

¹H-NMR (300 MHz, DMSO-d₆) δ: 2.01 (4H, m), 2.66 (2H, t, 6.87 Hz), 3.08(2H, t, 6.87 Hz), 3.62 (2H, m), 3.78 (2H, m), 3.87 (3H, s), 7.00 (1H,s), 7.43 (1H, s)

Example 525 Compound O29-Bromo-8-methoxy-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E2-1,the title compound was prepared as a crude product from Compound O1.

Example 526 Compound O39-Bromo-8-methoxy-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound O2.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.95 (2H, d, 14.87 Hz), 2.55 (2H, m), 4.04(2H, m), 4.09 (3H, s), 4.22 (2H, m), 7.51 (1H, s), 7.63 (1H, dd, 8.01Hz, 1.53 Hz), 8.09 (1H, s), 8.30 (1H, s), 8.36 (1H, d, 8.01 Hz), 12.3(1H, s).

LCMS: m/z 437, 439 [M+H]⁺

HPLC retention time: 2.65 min (analysis condition U)

Example 527 Compound O49-Fluoro-8-methoxy-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound O5-3,the title compound was prepared from Compound O3.

LCMS: m/z 377 [M+H]⁺

HPLC retention time: 2.29 min (analysis condition S)

Example 528 Compound O5-19-Fluoro-8-hydroxy-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound O4.

LCMS: m/z 363 [M+H]⁺

HPLC retention time: 1.88 min (analysis condition S)

Example 529 Compound O5-2 Trifluoromethanesulfonic Acid3-cyano-9-fluoro-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-8-yl

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound O5-1.

LCMS: m/z 495 [M+H]⁺

HPLC retention time: 3.47 min (analysis condition Y)

Example 530 Compound O5-39-Fluoro-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

To the THF (0.9 ml) solution of9-bromo-6-tetrahydropyran-8-pyrrolidinopiperidin-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound O8-1, 90 mg, 0.161 mmol), THF solution of n-butyl lithium (2 Msolution, 0.241 ml, 3 eq.) was added at −78° C. After stirring for 30min, THF (1 ml) solution of N— fluorobenzenesulfonimide (152 mg, 3 eq.)was added dropwise thereto. After rising to room temperature, themixture was stirred for 18 hr. To the reaction solution, water was addedand the extraction was carried out with ethyl acetate. The organic layerwas washed with brine and dried over magnesium sulfate. The drying agentwas removed by filtration and the residues obtained after concentrationunder reduced pressure were purified by high performance chromatographyto obtain the target compound (white solid, 0.44 mg, 0.5%).

¹H-NMR (CDCl₃+CD₃OD, 300 MHz): 1.75-1.94 (m, 11H), 2.02-2.01 (m, 2H),2.30-2.27 (m, 1H), 2.75-2.72 (m, 2H), 2.90-3.00 (m, 2H), 3.61-3.47 (m,4H), 4.01-3.90 (m, 4H), 7.08 (dd, 1H, J=1, 2 Hz, 8.4 Hz), 7.29 (dd, 1H,J=1, 5 Hz, 8.1 Hz), 7.68 (d, 1H, J=12.9 Hz), 7.72 (s, 1H), 8.22 (d, 1H,J=8.4 Hz)

LCMS: m/z 499 [M+H]⁺

HPLC retention time: 1.95 min (analysis condition U)

Example 531 Compound O5-48-(4-Cyclobutylpiperazin-1-yl)-9-fluoro-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound O5-2 and1-cyclobutylpiperazine.

LCMS: m/z 485 [M+H]⁺

HPLC retention time: 1.97 min (analysis condition U)

Example 532 Compound O6-19-Bromo-8-hydroxy-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound O3.

LCMS: m/z 423, 425 [M+H]⁺

HPLC retention time: 2.30 min (analysis condition U)

Example 533 Compound O6-2 Trifluoromethanesulfonic Acid9-bromo-3-cyano-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-8-yl

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound O6-1.

LCMS: m/z 555, 557 [M+H]⁺

HPLC retention time: 3.13 min (analysis condition U)

Example 534 Compound O7-19-Bromo-11-oxo-8-(piperazin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound O6-2 and piperazine.

LCMS: m/z 491, 493 [M+H]⁺

HPLC retention time: 1.88 min (analysis condition U)

Example 535 Compound O7-24-(9-Bromo-3-cyano-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-8-yl)piperazine-1-carboxylicAcid Tert-Butyl

To the dichloromethane (5 mL) solution of9-bromo-11-oxo-8-(piperazin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile(Compound 07-1, 250 mg, 0.509 mmol) and mono-tert-butyl ester carbonicanhydride (122 mg, 0.560 mmol), triethylamine (0.21 mL, 1.53 mmol) wasadded at 0° C., and stirred at room temperature for 1 hr. The reactionmixture was concentrated under reduced pressure and the residues werepurified by silica gel column chromatography (methanol/dichloromethane)to obtain the target compound as a white solid (212 mg, 70%).

¹H-NMR (300 MHz, DMSO-d₆) d ppm: 1.44 (9H, s), 1.97 (2H, m), 2.44 (2H,m), 1.35 (4H, m), 3.54 (4H, m), 4.06 (2H, m), 4.18 (2H, m), 7.57 (1H,s), 7.63 (1H, dd, 8.01 Hz, 1.52 Hz), 8.08 (1H, d, 1.52 Hz), 8.31 (1H,s), 8.36 (1H, d, 8.01 Hz), 12.3 (1H, s)

LCMS: m/z 591, 593 [M+H]⁺

HPLC retention time: 3.23 min (analysis condition T)

Example 536 Compound O7-3 Tert-butyl4-(3-cyano-11-oxo-9-(prop-1-ynyl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-8-yl)piperazine-1-carboxylicAcid

Under the same conditions as the method for synthesizing Compound O9-1,the title compound was prepared from Compound O7-2.

LCMS: m/z 551 [M+H]⁺

HPLC retention time: 3.92 min (analysis condition Y)

Example 537 Compound O7-411-Oxo-8-(piperazin-1-yl)-9-(prop-1-ynyl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound O7-3.

LCMS: 451 m/z [M+H]⁺

HPLC retention time: 1.87 min (analysis condition U)

Example 538 Compound O7-54-(3-Cyano-9-ethynyl-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-8-yl)piperazine-1-carboxylicacid tert-butyl

LCMS: m/z 537 [M+H]⁺

HPLC retention time: 3.82 min (analysis condition Y)

Example 539 Compound O8-19-Bromo-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound O6-2 and4-pyrrolidin-1-yl-piperidine.

LCMS: m/z 559, 561 [M+H]⁺

HPLC retention time: 2.05 min (analysis condition U)

Example 540 Compound O8-29-Bromo-8-(4-cyclobutylpiperazin-1-yl)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound O6-2 and1-cyclobutylpiperazine.

LCMS: m/z 547 [M+H]⁺

HPLC retention time: 1.61 min (analysis condition S)

Example 541 Compound O8-39-Bromo-8-(4-morpholinopiperidin-1-yl)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound O6-2 and4-piperidin-4-yl-morpholine.

LCMS: m/z 575, 577 [M+H]⁺

HPLC retention time: 1.95 min (analysis condition U)

Example 542 Compound O8-49-Bromo-8-(4-(oxetan-3-yl)piperazin-1-yl)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound O7-1 and oxetan-3-one.

LCMS: m/z 547, 549 [M+H]⁺

HPLC retention time: 1.43 min (analysis condition S)

Example 543 Compound O8-59-Bromo-8-(4-tert-butylpiperazin-1-yl)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound O6-2 and1-tert-butylpiperazine.

LCMS: 547, 549 m/z [M+H]⁺

HPLC retention time: 2.07 min (analysis condition U)

Example 544 Compound O9-111-Oxo-9-(prop-1-ynyl)-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

9-Bromo-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile(Compound O8-1, 100 mg, 0.170 mmol), tin tributyl(1-propynyl) (0.082 mL,0.268 mmol), bis(acetonitrile) palladium dichloride (II) (2.64 mg,0.00895 mmol), X-Phos (12.8 mg, 0.0269 mmol), and cesium carbonate(262.4 mg, 0.806 mmol) were suspended in acetonitrile (1 mL), and thenstirred at 80° C. for 2 hr. The reaction mixture was cooled to roomtemperature followed by addition of water and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The drying agent was removed byfiltration and the residues obtained after concentration under reducedpressure were purified by silica gel column chromatography(dichloromethane/methanol) to obtain the target compound (pale yellowsolid, 3.8 mg, 4.1%).

¹H-NMR (300 MHz, DMSO) σppm 12.20 (bs, 1H), 8.35 (d, 1H, J=8.1 Hz), 8.06(s, 1H), 8.06 (d, 1H, J=10.8 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.29 (s, 1H),4.25-4.23 (m, 2H), 4.02-3.98 (m, 2H), 3.78 (d, 2H, J=11.4 Hz), 2.93 (t,2H, J=11.1 Hz), 2.55 (s, 1H), 2.45-2.28 (m, 2H), 2.24-2.05 (m, 4H),2.08-1.81 (m, 4H), 1.75-1.50 (m, 7H)

LCMS: m/z 519 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition U)

Example 545 Compound O9-29-Ethynyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound O8-1.

LCMS: m/z 505 [M+H]⁺

HPLC retention time: 1.92 min (analysis condition U)

Example 546 Compound O9-311-Oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3,9-dicarbonitrile

Under the same conditions as the method for synthesizing Compound A5-2,the title compound was prepared from Compound O8-1.

LCMS: 506 m/z [M+H]⁺

HPLC retention time: 1.87 min (analysis condition U)

Example 547 Compound O9-49-(3-Hydroxy-3-methylbut-1-ynyl)-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundE4-2-1, the title compound was prepared from Compound O8-1.

LCMS: m/z 563 [M+H]⁺

HPLC retention time: 1.92 min (analysis condition U)

Example 548 Compound O9-58-(4-Cyclobutylpiperazin-1-yl)-11-oxo-9-(prop-1-ynyl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound O9-1,the title compound was prepared from Compound O8-2.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.6 (m, 2H), 1.8 (m, 2H), 1.9 (m, 4H), 2.1(s, 3H), 2.4 (m, 6H), 2.8 (m, 1H), 3.4 (m, 4H), 4.0 (m, 2H), 4.1 (m,2H), 7.3 (s, 1H), 7.6 (d, 1H, 8.0 Hz), 8.0 (m, 2H), 8.3 (d, 1H, 8.0 Hz),12.2 (s, 1H)

LCMS: m/z 505 [M+H]⁺

HPLC retention time: 2.03 min (analysis condition U)

Example 549 Compound O9-68-(4-Cyclobutylpiperazin-1-yl)-9-ethynyl-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from Compound O8-2.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.66 (2H, m), 1.83 (2H, t, 8.77 Hz), 1.99(4H, m), 2.41 (6H, m), 2.79 (1H, t, 7.63 Hz), 3.35 (4H, m), 4.01 (2H,m), 4.27 (2H, m), 4.51 (1H, s), 7.33 (1H, s), 7.54 (1H, m), 8.03 (1H,s), 8.16 (1H, s), 8.32 (1H, d, 8.40 Hz), 12.3 (1H, s).

LCMS: m/z 491 [M+H]⁺

HPLC retention time: 1.95 min (analysis condition U)

Example 550 Compound O9-78-(4-Morpholinopiperidin-1-yl)-1-oxo-9-(prop-1-ynyl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound O9-1,the title compound was prepared from Compound O8-3.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.57 (2H, m), 1.95 (4H, m), 2.14 (3H, s),2.37 (3H, m), 3.35 (4H, m), 2.83 (2H, t, 12.6 Hz), 3.56 (4H, s), 3.86(2H, d, 11.8 Hz), 4.04 (2H, m), 4.17 (2H, m), 7.31 (1H, s), 7.61 (1H, d,8.01 Hz), 8.06 (1H, s), 8.07 (1H, s), 8.36 (1H, d, 8.01 Hz), 12.3 (1H,s).

LCMS: m/z 535 [M+H]⁺

HPLC retention time: 1.95 min (analysis condition U)

Example 551 Compound O9-89-Ethynyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43,the title compound was prepared from compound 08-3.

LCMS: m/z 521 [M+H]⁺

HPLC retention time: 1.90 min (analysis condition U)

Example 552 Compound O9-98-(4-(Oxetan-3-yl)piperazin-1-yl)-11-oxo-9-(prop-1-ynyl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound O7-4 and oxetan-3-one.

LCMS: m/z 507 [M+H]⁺

HPLC retention time: 1.43 min (analysis condition S)

Example 553 Compound O10-1-1

Tert-butyl4-(3-cyano-9-ethyl-11-oxo-2′,3′,5,5a,5′,6′,11,11a-octahydrospiro[benzo[b]carbazole-6,4′-pyran]-8-yl)piperazine-1-carboxylicacid

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound O7-5.

LCMS: m/z 541 [M+H]⁺

HPLC retention time: 3.08 min (analysis condition S)

Example 554 Compound O10-1-29-Ethyl-11-oxo-8-(piperazin-1-yl)-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound O10-1-1.

LCMS: m/z 441 [M+H]⁺

HPLC retention time: 1.42 min (analysis condition S)

Example 555 Compound O10-29-Ethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

According to the same method as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound O9-8.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.23-8.21 (1H, m), 8.02-8.00 (1H, m),7.88-7.86 (1H, m), 7.39-7.36 (2H, m), 4.63-4.59 (2H, m), 3.89-3.85 (2H,m), 3.60-3.56 (6H, m), 3.22-3.19 (4H, m), 2.76-2.68 (4H, m), 2.37-2.32(3H, m), 1.92-1.88 (2H, m), 1.75-1.72 (2H, m), 1.61-1.57 (2H, m),1.27-1.25 (3H, m)

LCMS: m/z 525 [M+H]⁺

HPLC retention time: 1.48 min (analysis condition S)

Example 556 Compound O10-39-Ethyl-8-(4-(oxetan-3-yl)piperazin-1-yl)-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound O10-1-2 and oxetan-3-one.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.26 (1H, s), 8.39 (1H, d, 7.9 Hz),8.09-8.07 (2H, m), 7.63 (1H, d, 8.5 Hz), 7.51 (1H, s), 4.60-4.50 (4H,m), 4.20-4.09 (4H, m), 3.56-3.51 (1H, m), 3.07-3.05 (4H, m), 2.76-2.70(2H, m), 2.44-2.40 (2H, m), 2.02-1.98 (2H, m), 1.29-1.26 (4H, m)

LCMS: m/z 497 [M+H]⁺

HPLC retention time: 1.42 min (analysis condition S)

Example 557 Compound O10-48-(4-Cyclobutylpiperazin-1-yl)-9-ethyl-11-oxo-2′,3′,5,5′,6′,11-hexahydrospiro[benzo[b]carbazole-6,4′-pyran]-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound O10-1-2 and cyclobutanone.

LCMS: m/z 495 [M+H]⁺

HPLC retention time: 1.57 min (analysis condition S)

Example 558 Compound P1 (Intermediate)8-Methoxy-6,6-dimethyl-2-nitro-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A3-1,the title compound was prepared from Compound A2 and4-nitrophenylhydrazine.

LCMS: m/z 323 [M+H]⁺

HPLC retention time: 4.08 min (analysis condition W)

Example 559 Compound P2 (Intermediate)8-Methoxy-6,6-dimethyl-2-nitro-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound P1.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.85 (1H, s), 9.03 (1H, d, J=1.9 Hz),8.17-8.20 (2H, m), 7.71 (1H, d, J=9.1 Hz), 7.38 (1H, d, J=2.4 Hz), 7.12(1H, dd, J=8.5, 2.4 Hz), 3.93 (3H, s), 1.79 (6H, s)

LCMS: m/z 337 [M+H]⁺

HPLC retention time: 3.55 min (analysis condition W)

Example 560 Compound P3 (Intermediate)8-Hydroxy-6,6-dimethyl-2-nitro-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound P2.

LCMS: m/z 323 [M+H]⁺

HPLC retention time: 3.11 min (analysis condition W)

Example 561 Compound P4 (Intermediate)4-(6,6-Dimethyl-2-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-piperidine-1-Carboxylic Acid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound P3.

¹H-NMR (400 MHz, CDCl₃) δ: 9.40 (1H, s), 9.37 (1H, s), 8.41 (1H, d,J=8.5 Hz), 8.24 (1H, d, J=11.0 Hz), 7.51 (1H, d, J=8.5 Hz), 7.13 (1H,s), 7.03 (1H, d, J=9.1 Hz), 4.61-4.71 (1H, m), 3.69-3.84 (2H, m),3.35-3.49 (2H, m), 1.94-2.10 (2H, m), 1.75-1.93 (8H, m), 1.50 (9H, s)

LCMS: m/z 506 [M+H]⁺

HPLC retention time: 4.17 min (analysis condition W)

Example 562 Compound P52-Amino-6,6-dimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound P6.

¹H-NMR (400 MHz, CD₃OD) δ: 8.23 (1H, d, J=8.5 Hz), 7.68 (1H, d, J=2.4Hz), 7.26 (1H, d, J=8.5 Hz), 7.24 (1H, d, J=2.4 Hz), 7.06 (1H, dd,J=8.5, 2.4 Hz), 6.80 (1H, dd, J=8.5, 2.4 Hz), 4.64-4.71 (1H, m),3.06-3.15 (2H, m), 2.73-2.83 (2H, m), 2.02-2.13 (2H, m), 1.67-1.82 (8H,m)

LCMS: m/z 506 [M+H]⁺

HPLC retention time: 4.17 min (analysis condition W)

Example 563 Compound P6 (Intermediate)4-(2-Amino-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-piperidine-1-carboxylic Acid Tert-Butyl Ester

To the ethanol (8 ml) suspension of4-(6,6-dimethyl-2-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound P4, 103 mg,0.204 mmol), iron powder (228 mg, 20 eq.), ammonium chloride (109 mg, 10eq.), and distilled water (4 ml) were added and the mixture was stirredat 90° C. for 30 min. Upon the completion of the reaction, insolublematters were filtered off, and the filtrate was extracted with ethylacetate. The organic layer was washed with brine and dried over sodiumsulfate. The drying agent was removed by filtration and the residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (115 mg, 57%).

LCMS: m/z 476 [M+H]⁺

HPLC retention time: 2.82 min (analysis condition W)

Example 564 Compound P7 (Intermediate)4-(2-Methanesulfonylamino-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-piperidine-1-carboxylic Acid Tert-Butyl Ester

To the pyridine (2 ml) solution of4-(2-amino-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound P6, 50 mg,0.105 mmol), mesyl chloride (9 μl, 1.2 eq.) was added and stirred atroom temperature for 30 min. Upon the completion of the reaction, thereaction solution was concentrated under reduced pressure to obtain thetitle compound as an unpurified product.

LCMS: m/z 554 [M+H]⁺

HPLC retention time: 3.60 min (analysis condition W)

Example 565 Compound P8N-[6,6-Dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-2-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound P7.

¹H-NMR (400 MHz, CD₃OD) δ: 8.25 (1H, d, J=8.5 Hz), 8.16 (1H, d, J=1.8Hz), 7.46 (1H, d, J=9.1 Hz), 7.27-7.29 (2H, m), 7.09 (1H, dd, J=9.1, 1.8Hz), 4.67-4.75 (1H, m), 3.09-3.18 (2H, m), 2.95 (3H, s), 2.77-2.87 (2H,m), 1.70-1.84 (8H, m)

LCMS: m/z 454 [M+H]⁺

HPLC retention time: 2.22 min (analysis condition W)

Example 566 Compound Q3 (Intermediate)2-Fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A3-1,the title compound was prepared from Compound A2 and3-cyano-4-fluorophenylhydrazine.

LCMS: m/z 321 [M+H]⁺

HPLC retention time: 4.13 min (analysis condition W)

Example 567 Compound Q4 (Intermediate)2-Fluoro-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound Q3.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.89 (1H, s), 8.16 (1H, d, J=8.5 Hz), 8.07(1H, d, J=4.9 Hz), 8.04 (1H, d, J=9.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.10(1H, dd, J=8.5, 2.4 Hz), 3.91 (3H, s), 1.78 (3H, s)

LCMS: m/z 335 [M+H]⁺

HPLC retention time: 3.61 min (analysis condition W)

Example 568 Compound Q5 (Intermediate)2-Fluoro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound Q4.

LCMS: m/z 321 [M+H]⁺

HPLC retention time: 3.16 min (analysis condition W)

Example 569 Compound Q6 (Intermediate)4-(3-Cyano-2-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-piperidine-1-carboxylic Acid Tert-Butyl Ester

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound Q5.

LCMS: m/z 504 [M+H]⁺

HPLC retention time: 4.25 min (analysis condition W)

Example 570 Compound Q78-(2-Diethylamino-ethoxy)-2-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound Q5.

¹H-NMR (400 MHz, CD₃OD) δ: 8.25 (1H, d, J=8.5 Hz), 8.09 (1H, d, J=9.8Hz), 7.83 (1H, d, J=5.5 Hz), 7.30 (1H, d, J=2.4 Hz), 7.09 (1H, dd,J=8.5, 2.4 Hz), 4.26 (2H, t, J=5.7 Hz), 2.98 (2H, t, J=5.7 Hz), 2.72(4H, q, J=7.2 Hz), 1.81 (6H, s), 1.13 (6H, t, J=7.2 Hz)

LCMS: m/z 420 [M+H]⁺

HPLC retention time: 2.65 min (analysis condition W)

Example 571 Compound Q82-Fluoro-6,6-dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from Compound Q6.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.11 (1H, d, J=8.5 Hz), 7.98 (1H, d, J=5.5Hz), 7.96 (1H, d, J=9.8 Hz), 7.29 (1H, s), 7.08 (1H, d, J=8.5 Hz),4.58-4.69 (1H, m), 2.93-3.05 (2H, m), 2.60-2.69 (2H, m), 1.94-2.03 (2H,m), 1.74 (6H, s), 1.45-1.57 (2H, m)

LCMS: m/z 404 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition W)

Example 572 Compound R2 2-Fluoro-3-hydrazinylbenzonitrile

3-Amino-2-fluoro-benzonitrile (100 mg, 0.735 mmol) was dissolved inwater (0.94 mL), added with conc. hydrochloric acid (0.74 mL) at 0° C.,and then further added with an aqueous solution (0.294 mL) of sodiumnitrite (61 mg, 0.882 mmol). The resulting mixture was stirred at 0° C.for 1 hr. To the reaction mixture, conc. hydrochloric acid solution(0.94 mL) of tin chloride (321 mg, 1.69 mmol) was added and stirred atroom temperature for 1 hr. Thereafter, the reaction solution wasneutralized with aqueous solution of sodium hydroxide, and extractedwith dichloromethane. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate. The drying agent was removedby filtration and the residues were obtained after concentration underreduced pressure to give the target compound as a crude product.

Example 573 Compound R34-Fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E2-1,the title compound was prepared as a crude product from Compound A2 andCompound R2.

Example 574 Compound R44-Fluoro-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4,the title compound was prepared from Compound R3.

LCMS: m/z 335 [M+H]⁺

HPLC retention time: 2.70 min (analysis condition U)

Example 575 Compound R54-Fluoro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound R4.

LCMS: m/z 321 [M+H]⁺

HPLC retention time: 2.32 min (analysis condition U)

Example 576 Compound R68-(2-Diethylamino-ethoxy)-4-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound R5.

LCMS: m/z 420 [M+H]⁺

HPLC retention time: 1.51 min (analysis condition S)

Example 577 Compound R7 Trifluoromethanesulfonic Acid3-cyano-4-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound R5.

LCMS: m/z 453 [M+H]⁺

HPLC retention time: 3.82 min (analysis condition Y)

Example 578 Compound R8-14-Fluoro-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound R7 and4-pyrrolidin-1-yl-piperidine.

LCMS: m/z 457 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition U)

Example 579 Compound R8-24-Fluoro-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound R7.

LCMS: m/z 431 [M+H]⁺

HPLC retention time: 2.07 min (analysis condition U)

Example 580 Compound R9-1 8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-4-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared as a crude product from Compound R5 and(R)-(−)-2,2-dimethyl-1,3-dioxolan-4-methanol.

Example 581 Compound R9-28-((R)-2,3-Dihydroxy-propoxy)-4-fluoro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound R9-1 (9.9 mg,80%).

LCMS: m/z 395 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition C)

Example 582 Compound S1-13-Chloro-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A3-1and Compound A4, the title compound was prepared as a crude product fromCompound A2 and (3-chlorophenyl)-hydrazine hydrochloric acid salt

Example 583 Compound S1-23-Chloro-8-methoxy-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,99.1 mg, 0.485 mmol) and (3-chloro-4-methyl-phenyl)hydrazinehydrochloric acid salt (100.4 mg, 1.1 eq.) were dissolved in TFA (1 mL)and the mixture was irradiated with microwave at 80° C. for 10 min undernitrogen atmosphere. After cooling, the reaction solution was added withethyl acetate, washed with water, saturated aqueous solution of sodiumhydrogen carbonate and saturated brine and dried over magnesium sulfate.After filtration and concentration under reduced pressure, the residuesobtained therefrom were dissolved in THF (2 mL) and water (0.2 mL),added with DDQ (125.7 mg, 1.1 eq.), and stirred at room temperatureovernight. The reaction solution was added with the mixture solvent ofhexane and ethyl acetate, and the starting-point components were removedby dry type silica gel column. The eluent was concentrated under reducedpressure, and the resulting residues were purified by preparative TLC(methanol/dichloromethane) to obtain the title compound (19.4 mg, 12%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.2 (1H, s), 8.15 (1H, d, J=8.8 Hz), 8.12(1H, s), 7.52 (1H, s), 7.32 (1H, s), 7.07 (1H, dd, J=2.4, 8.8 Hz), 3.90(3H, s), 2.45 (3H, s), 1.73 (6H, s),

LCMS: m/z 340 [M+H]⁺

HPLC retention time: 2.80 min (analysis condition F)

Example 584 Compound S1-33-Chloro-4-fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA3-1, the title compound was prepared from Compound A2 and(3-chloro-2-fluoro-phenyl)-hydrazine.

LCMS: m/z 344, 346 [M+H]⁺

HPLC retention time: 2.68 min (analysis condition S)

Example 585 Compound S1-49-Bromo-3-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (CompoundE1, 0.2 g, 0.71 mmol) and 3-chlorophenylhydrazine hydrochloric acid salt(0.17 g, 1.3 eq.) were dissolved in acetic acid (0.5 mL). Under nitrogenatmosphere, the reaction solution was stirred at 90° C. for 8 hr. Aftercooling to room temperature, the reaction solution was added with ethylacetate, washed with water, saturated aqueous solution of sodiumhydrogen carbonate and saturated brine and dried over magnesium sulfate.After filtration and concentration under reduced pressure, the residuesobtained therefrom were dissolved in THF (3 mL) comprising 10% water,added with DDQ (227 mg, 3 eq.) at room temperature, and the mixture wasstirred at room temperature for 2 hr. The reaction solution was addedwith the mixture liquid of THF/diethyl ether (1:1) and washed with 0.5 Naqueous solution of sodium hydroxide and saturated brine. After dryingwith sodium sulfate, the mixture was filtered and the resulting residuesobtained after concentration under reduced pressure were washed with themixture liquid of hexane/diethyl ether (1:1) to obtain the titlecompound (brown powder, 86 mg).

LCMS: m/z 404, 406, 408 [M+H]⁺

HPLC retention time: 3.02 min (analysis condition C)

Example 586 Compound S2-13-Chloro-8-hydroxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound S1-1.

LCMS: m/z 312 [M+H]⁺

HPLC retention time: 4.18 min (analysis condition H)

Example 587 Compound S2-23-Chloro-8-hydroxy-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Chloro-8-methoxy-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound S1-2, 18.9 mg, 0.0556 mmol) and pyridinium chloride (220 mg,34 eq.) were stirred at 185° C. for 2.5 hr. After cooling, the reactionsolution was added with water and ethyl acetate, and the organic layerwas washed with water and saturated brine, dried over magnesium sulfate,filtered and concentrated under reduced pressure to obtain the titlecompound as a crude product.

Example 588 Compound S2-33-Chloro-4-fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Chloro-4-fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound S1-3, 220.0 mg, 0.640 mmol) and pyridinium chloride (800 mg,6.922 mmol) were mixed with each other, heated to 160° C., and thenstirred for 20 hr. The reaction solution was added with water. As aresult, black solid was obtained as a precipitate, which was thenfiltered and subjected to purification by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound(139.4 mg, 66%).

LCMS: m/z 330 [M+H]⁺

HPLC retention time: 2.60 min (analysis condition F)

Example 589 Compound S2-49-Bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound S1-4.

LCMS: m/z 390, 392, 394 [M+H]⁺

HPLC retention time: 2.75 min (analysis condition C)

Example 590 Compound S33-Chloro-8-(2-diethylaminoethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(CH5263231-000)

3-Chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound S2-1, 10 mg, 0.03207 mmol) was dissolved in DMF (0.1 mL),added with (2-chloroethyl)diethylamine (5.5 mg, 0.03207 mmol) and cesiumcarbonate (20.9 mg, 0.06414 mmol), and stirred at 80° C. for 2 hr. Thereaction solution was added to water and extracted with ethyl acetate.The organic layer was dried over magnesium sulfate. The residuesobtained after concentration under reduced pressure were purified by NHsilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (11.6 mg, 76%).

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 4.49 min (analysis condition H)

Example 591 Compound S43-Chloro-2,6,6-trimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[b]carbazol-11-one

Crude product of Compound S2-2 was dissolved in THF (0.4 mL) undernitrogen atmosphere, together with THF (0.2 mL) solution oftriphenylphosphine (18.9 mg, 1.3 eq.) and[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol(17 mg, 1.2 eq.). DEAD (40% toluene solution, 0.0031 mL, 1.2 eq.) wasadded to the solution, which was then stirred at room temperature for 40min and at 40° C. for 4 hr. The reaction solution was added withtriphenylphosphine (18.9 mg, 1.3 eq.) and DEAD (40% toluene solution,0.002 mL, 0.8 eq.) and stirred at 40° C. overnight. The reactionsolution was added with ethyl acetate, washed with water and saturatedbrine, dried over magnesium sulfate, and filtered. The residues obtainedafter concentration under reduced pressure were purified by praparativeTLC (ethyl acetate/hexane) to obtain the crude product of8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-chloro-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one(12.6 mg).

The resultant was dissolved in THF (0.15 mL) and methanol (0.03 mL)under nitrogen atmosphere, added with 0.5 M sulfuric acid (0.05 mL) andstirred at 60° C. for 3 hr. After cooling, diethyl ether was added andsodium hydrogen carbonate (8.4 mg) and water were further added thereto.The organic layer was washed with saturated brine. The aqueous layer wasextracted with ethyl acetate, and the combined organic layer was driedover magnesium sulfate, and filtered. The solid obtained from theconcentration under reduced pressure was washed with dichloromethane toobtain the target compound (white solid, 5.3 mg, 22%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.18 (1H, s), 8.14 (1H, d, J=8.8 Hz), 8.12(1H, s), 7.52 (1H, s), 7.31 (1H, d, J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8Hz), 4.78 (1H, d, J=5.9 Hz), 4.60 (1H, d, J=5.9 Hz), 4.52 (1H, t, J=5.4Hz), 4.18-4.22 (1H, m), 4.02-4.06 (1H, m), 3.85-3.95 (1H, m), 3.50-3.60(2H, m), 3.40-3.46 (1H, m), 2.45 (3H, s), 1.73 (3H, s),

LCMS: m/z 430 [M+H]⁺

HPLC retention time: 2.27 min (analysis condition F)

Example 592 Compound S53-Chloro-8-ethoxy-4-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

The title compound was obtained as a by-product of the synthesis ofCompound S6.

LCMS: m/z 358 [M+H]⁺

HPLC retention time: 3.16 min (analysis condition F)

Example 593 Compound S63-Chloro-8-((R)-2,3-dihydroxy-propoxy)-4-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Chloro-4-fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound S2-3, 20.0 mg, 0.061 mmol) was dissolved in THF (0.25 mL),added with ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (9.8 μL, 0.079mmol), triphenylphosphine (20.7 mg, 0.079 mmol) and diethylazodicarboxylic acid (35.9 μl, 0.079 mmol), and then stirred at 40° C.for 5 hr. The reaction solution was concentrated under reduced pressure,and the resulting residues were purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the intermediate,3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-4-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one. Thiscompound was dissolved in THF (0.10 mL) and MeOH (0.08 ml), added withsulfuric acid (0.5 M, 0.045 ml), and then stirred at 60° C. for 1 hr.The reaction solution was added with saturated aqueous solution ofsodium hydrogen carbonate, extracted with ethyl acetate and dried overanhydrous magnesium sulfate. The yellow solid obtained afterconcentration under reduced pressure was washed with methylenechloride/hexane solvent and filtered to obtain the title compound (4.3mg, 18%).

LCMS: m/z 404 [M+H]⁺

HPLC retention time: 2.34 min (analysis condition F)

Example 594 Compound S7-13-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere,9-bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound S2-4, 76 mg, 0.2 mmol) and triphenylphosphine (69 mg, 1.3 eq.)were added with THF (2 ml), and((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (35 mg, 1.3 eq.) and 2.19N toluene solution (118 μL, 1.3 eq.) of diethyl azodicarboxylic acidwere added dropwise thereto, followed by stirring at 50° C. for 2 hr.After cooling, the reaction solution was added with ethyl acetate,washed with brine, dried over sodium sulfate and filtered. The residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (ethyl acetate/dichloromethane) to givea solid, which was then washed with dichloromethane to obtain the titlecompound (brown powder, 53 mg).

LCMS: m/z 504, 506, 508 [M+H]⁺

HPLC retention time: 3.17 min (analysis condition C)

Example 595 Compound S7-29-Bromo-3-chloro-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundS7-1, 56 mg, 0.11 mmol) was dissolved in methanol (5 mL), added with 1 Nhydrochloric acid (0.2 ml), and stirred at 50° C. for 2 hr. Aftercooling, the reaction solution was concentrated under reduced pressureand the resulting residues were added with methanol to obtain aprecipitated solid, which was then filtered to obtain the title compound(white powder, 26 mg).

LCMS: m/z 464, 466, 468 [M+H]⁺

HPLC retention time: 2.77 min (analysis condition C)

Example 596 Compound S7-33-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere,9-bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound S2-4, 112 mg, 0.29 mmol) and triphenylphosphine (227 mg, 3eq.) were added with THF (2 ml), and((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (114 mg, 3 eq.) and 2.19N toluene solution (0.4 mL, 3 eq.) of diethyl azodicarboxylic acid wereadded dropwise thereto, followed by stirring at 40° C. for 12 hr undernitrogen atmosphere. The residues obtained from the reaction solutionafter concentration under reduced pressure were purified by silica gelcolumn chromatography (ethyl acetate/dichloromethane) to obtain thetitle compound (white powder, 100 mg).

LCMS: m/z 504, 506, 508 [M+H]⁺

HPLC retention time: 3.15 min (analysis condition C)

Example 597 Compound S7-49-Bromo-3-chloro-8-((S)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound S7-2,the title compound was prepared from Compound S7-3.

LCMS: m/z 464, 466, 468 [M+H]⁺

HPLC retention time: 2.77 min (analysis condition C)

Example 598 Compound S8-19-Hydroxy-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

9-Bromo-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundS7-1, 30 mg, 0.06 mmol) was dissolved in the mixture solvent ofwater⋅dioxane (1:1) (0.5 mL), added with tris(benzylidenacetonedipalladium)chloroform complex (3.1 mg, 0.05 eq.),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (2.5 mg, 0.1 eq.)and KOH (0.5 N aqueous solution 180 μL, 1.5 eq.), and stirred at 60° C.for 12 hr. After cooling, the reaction solution was concentrated underreduced pressure, and the resulting residues were purified by HPLC toobtain the title compound (white solid, 4.6 mg).

LCMS: m/z 442, 444 [M+H]

HPLC retention time: 2.78 min (analysis condition C)

Example 599 Compound S8-23-Chloro-8-((R)-2,3-dihydroxy-propoxy)-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound S7-2,the title compound was prepared from Compound S8-1.

LCMS: m/z 402, 404 [M+H]

HPLC retention time: 0.90 min (analysis condition I)

Example 600 Compound S9-18-Hydroxy-6,6-dimethyl-11-oxo-9-(1H-tetrazol-5-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Bromo-3-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound S1-4, 150 mg, 0.37 mMol) was dissolved in NMP, added with CuCN(100 mg, 3 eq.), and stirred at 210° C. for 1.5 hr under irradiationwith microwave. After cooling, the reaction solution was added withwater and ethyl acetate, and the precipitated solid was filtered toremove the solvent. The obtained residues were dissolved in DMF (1 ml),added with sodium azide (100 mg, 8 eq.) and ammonium chloride (5 mg),and then stirred at 120° C. for 24 hr in a sealed tube. After addingwater, the insoluble matters were filtered and purified by HPLC toobtain the title compound (6.5 mg).

LCMS: m/z 371 [M+H]⁺

HPLC retention time: 2.22 min (analysis condition C)

Example 601 Compound S9-23-Chloro-8-hydroxy-6,6-dimethyl-9-(1H-tetrazol-5-yl)-5,6-dihydro-benzo[b]carbazol-11-one

The title compound was obtained as an intermediate for the synthesis ofCompound S9-1

LCMS: m/z 380, 382 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition C)

Example 602 Compound S103-Chloro-8-((R)-2,3-dihydroxy-propoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

To the mixture of9-bromo-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-1-one (Compound S7-1,50 mg, 0.1 mmol), bis(acetonitrile) palladium (II) dichloride (2.6 mg,0.01 eq.), cesium carbonate (195 mg, 6 eq.) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (14.3 mg, 0.03eq.), acetonitrile (2 mL) was added and stirred at 80° C. for 12 hr.Tar-like residues obtained after concentration under reduced pressurewere purified by silica gel column chromatography (ethyl acetate/hexane)to obtain 3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(brown powder, 105 mg).

The resulting 3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(20 mg, 0.04 mmol) was dissolved in methanol (3 mL), added with 1 Nhydrochloric acid (1 ml), and stirred at room temperature for 12 hr.After cooling, the reaction solution was concentrated under reducedpressure, and the resulting residues were washed with methylene chlorideto obtain the title compound (pale yellow powder, 5.2 mg).

LCMS: m/z 468, 470 [M+H]⁺

HPLC retention time: 2.70 min (analysis condition C)

Example 603 Compound S11-13-Chloro-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile

3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundS7-2, 17 mg, 37 μmol) was dissolved in DMA, added with CuCN (17 mg, 5eq.), and stirred at 220° C. for 2 hr under irradiation with microwave.After cooling, the reaction solution was added with ethyl acetate, andthe precipitated solid was filtered to remove the solvent. The resultingresidues were purified by HPLC to obtain the title compound (4 mg).

LCMS: m/z 409, 411 [M+H]⁺

HPLC retention time: 2.65 min (analysis condition C)

Example 604 Compound S11-23-Chloro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile

The title compound was obtained as a by-product of the synthesis ofCompound S11-1.

LCMS: m/z 337, 339 [M+H]⁺

HPLC retention time: 2.35 min (analysis condition C)

Example 605 Compound T1-13-Bromo-6,6-dimethyl-8-[(R)-(tetrahydro-furan-3-yl)oxy]-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 and(S)-tetrahydro-furan-3-ol.

LCMS: m/z 426 [M+H]⁺

HPLC retention time: 2.08 min (analysis condition D)

Example 606 Compound T1-26,6-Dimethyl-11-oxo-8-[(R)-(tetrahydro-furan-3-yl)oxy]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA5-2, the title compound was prepared from Compound T1-1.

LCMS: m/z 373 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition A)

Example 607 Compound T2-13-Bromo-6,6-dimethyl-8-[(S)-(tetrahydro-furan-3-yl)oxy]-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 and(R)-tetrahydro-furan-3-ol.

LCMS: m/z 426 [M+H]⁺

HPLC retention time: 6.12 min (analysis condition H)

Example 608 Compound T2-26,6-Dimethyl-11-oxo-8-[(S)-(tetrahydro-furan-3-yl)oxy]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing CompoundA5-2, the title compound was prepared from Compound T2-1.

LCMS: m/z 373 [M+H]⁺

HPLC retention time: 2.00 min (analysis condition D)

Example 609 Compound T3-1 3-Bromo-6,6-dimethyl-8-(tetrahydro-pyran-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 andtetrahydro-pyran-4-ol.

LCMS: m/z 440 [M+H]⁺

HPLC retention time: 8.07 min (analysis condition H)

Example 610 Compound T3-23-Bromo-5,6,6-trimethyl-8-(tetrahydro-pyran-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA10-2, the title compound was prepared from Compound T3-1.

LCMS: m/z 454 [M+H]⁺

HPLC retention time: 6.88 min (analysis condition H)

Example 611 Compound T4-13-Bromo-6,6-dimethyl-8-(2-phenyl-[1,3]dioxan-5-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 and5-phenyl-[1,3]dioxan-2-ol.

LCMS: m/z 518 [M+H]⁺

HPLC retention time: 2.68 min (analysis condition D)

Example 612 Compound T4-23-Bromo-8-(2-hydroxy-1-hydroxymethyl-ethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-13-2, the title compound was prepared from Compound T4-1.

LCMS: m/z 430 [M+H]⁺

HPLC retention time: 4.64 min (analysis condition H)

Example 613 Compound T5-14-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-piperidine-1-carboxylic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 and4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 539 [M+H]⁺

HPLC retention time: 2.72 min (analysis condition D)

Example 614 Compound T5-24-(3-Bromo-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-piperidine-1-carboxylic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundA10-1, the title compound was prepared from Compound T5-1.

LCMS: m/z 553 [M+H]⁺

HPLC retention time: 2.93 min (analysis condition D)

Example 615 Compound T5-33-Bromo-5,6,6-trimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA8-1, the title compound was prepared from Compound T5-2.

LCMS: m/z 453 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition D)

Example 616 Compound T5-43-Bromo-8-(1-methanesulfonyl-piperidin-4-yloxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-7, the title compound was prepared from Compound T5-3 andmethanesulfonyl chloride.

LCMS: m/z 531 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition D)

Example 617 Compound T5-58-(1-Acetyl-piperidin-4-yloxy)-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T5-3 and aceticanhydride.

LCMS: m/z 482 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition D)

Example 618 Compound T6-13-Bromo-6,6-dimethyl-8-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yloxy]-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T6-2 andtrifluoroacetic anhydride.

LCMS: m/z 535 [M+H]⁺

HPLC retention time: 2.53 min (analysis condition D)

Example 619 Compound T6-23-Bromo-6,6-dimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-6,6-dimethyl-8-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yloxy]-5,6-dihydro-benzo[b]carbazol-11-one(Compound T6-1, 28.0 mg, 52.3 μmol) was dissolved in THF (1.00 mL) andmethanol (0.50 mL), added with aqueous solution of potassium hydroxide(1.00 mL, 20 wt %), and stirred at room temperature for 1 hr. Thereaction solution was added to water, and extracted with mixturesolution of chloroform and methanol, and dried over sodium sulfate.Then, after filtering and concentration under reduced pressure,3-bromo-6,6-dimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-onewas obtained as a crude product.

LCMS: m/z 439 [M+H]⁺

HPLC retention time: 1.83 min (analysis condition D)

Example 620 Compound T6-33-Bromo-8-(1-methanesulfonyl-piperidin-4-yloxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T6-2 and mesylchloride.

LCMS: m/z 517 [M+H]⁺

HPLC retention time: 2.23 min (analysis condition D)

Example 621 Compound T6-48-(1-Acetyl-piperidin-4-yloxy)-3-bromo-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T6-2 and aceticanhydride.

LCMS: m/z 496 [M+H]⁺

HPLC retention time: 2.27 min (analysis condition D)

Example 622 Compound T7-13-Bromo-8-isopropoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

The title compound was obtained as a by-product of the synthesis ofCompound T4-1.

LCMS: m/z 398 [M+H]⁺

HPLC retention time: 3.18 min (analysis condition F)

Example 623 Compound T7-23-Bromo-8-isopropoxy-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA10-2, the title compound was prepared from Compound T7-1.

LCMS: m/z 413 [M+H]⁺

HPLC retention time: 2.70 min (analysis condition D)

Example 624 Compound T8-1 3-Bromo-5,6,6-trimethyl-8-(2-phenyl-[1,3]dioxan-5-yl oxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA10-2, the title compound was prepared from Compound T4-1.

LCMS: m/z 532 [M+H]⁺

HPLC retention time: 2.90 min (analysis condition D)

Example 625 Compound T8-23-Bromo-8-(2-hydroxy-1-hydroxymethyl-ethoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-13-2, the title compound was prepared from Compound T4-1.

LCMS: m/z 444 [M+H]⁺

HPLC retention time: 1.90 min (analysis condition D)

Example 626 Compound T9N-[2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-ethyl]-acetamide

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound A5-1 and(N-(2-chloro-ethyl)-acetamide.

LCMS: m/z 441 [M+H]⁺

HPLC retention time: 1.92 min (analysis condition D)

Example 627 Compound T10 3-Bromo-6,6-dimethyl-8-(oxetan-3-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound A5-1 andtoluene-4-sulfonic acid oxetan-3-yl ester.

LCMS: m/z 412 [M+H]⁺

HPLC retention time: 2.17 min (analysis condition D)

Example 628 Compound T11 3-Bromo-8-(4-hydroxy-tetrahydro-furan-3-yloxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, tetrahydro-furo[3,4-d] [1,3,2]dioxathiol2,2-dioxide (71.5 mg, 0.420 mmol) was dissolved in DMF (1.40 mL), addedwith 3-bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound A5-1, 50.0 mg, 0.140 mmol) and cesium carbonate (228 mg, 0.700mmol), and stirred at 80° C. for 15 hr. Subsequently, sulfuric acid(0.10 mL, 18 M), THF (3.00 mL) and water (0.50 mL) were added to themixture, which was then stirred at room temperature for 24 hr andfurther at 60° C. for 24 hr. The reaction solution was added to water,extracted with ethyl acetate, washed with water, saturated aqueoussolution of sodium bicarbonate, and saturated brine, and dried oversodium sulfate. After filtering and concentration under reducedpressure, the resulting residues were washed with dichloromethane andpurified by NH silica gel column chromatography (ethyl acetate/THF) toobtain the target compound (44.7 mg, 72%).

LCMS: m/z 442 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition D)

Example 629 Compound T12-1 Acetic acid(2S,3R,4S,5R,6R)-4,5-diacetoxy-6-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxymethyl)-2-methoxy-tetrahydro-pyran-3-yl Ester

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 and methyl2,3,4-tri-O-acetyl-α-D-glucopyranoside.

LCMS: m/z 658 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition D)

Example 630 Compound T12-23-Bromo-6,6-dimethyl-8-((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxy-tetrahydro-pyran-2-ylmethoxy)-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to acetic acid(2S,3R,4S,5R,6R)-4,5-diacetoxy-6-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxymethyl)-2-methoxy-tetrahydro-pyran-3-yl ester (Compound T12-1, 34.0mg, 51.63 μmol), methanol solution (2.50 mL, 2 M) of ammonia was added,and the mixture was stirred at room temperature for 21 hr. The reactionsolution was concentrated under reduced pressure, and the resultingresides were washed with diethyl ether to obtain the target compound(25.7 mg, 94%).

LCMS: m/z 532 [M+H]⁺

HPLC retention time: 2.42 min (analysis condition D)

Example 631 Compound T13-1(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-acetic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound A5-1 andbromo-acetic acid tert-butyl ester.

LCMS: m/z 470 [M+H]⁺

HPLC retention time: 2.53 min (analysis condition D)

Example 632 Compound T13-2(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-acetic Acid

According to the same method as the method for synthesizing CompoundA8-1, the title compound was prepared from Compound T13-1.

LCMS: m/z 414 [M+H]⁺

HPLC retention time: 1.50 min (analysis condition D)

Example 633 Compound T13-32-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-N-(3-ethyl-3-hydroxy-pentyl)-acetamide

Under nitrogen atmosphere,(3-azide-1,1-diethyl-propoxy)-trimethyl-silane (16.6 mg, 72.42 μmol) wasdissolved in toluene (0.48 mL), added with3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-acetic acid (20.0 mg, 48.28 μmol) and Molecular Sieves 4 angstrom,and the mixture was stirred at room temperature for 5 min. Thereafter,the mixture was added with trimethylphosphine (10.2 μL, 96.56 μmol) andstirred at 80° C. for 22 hr. The reaction solution was added tohydrochloric acid (1 M), extracted with ethyl acetate, washed withwater, saturated aqueous solution of sodium bicarbonate, saturated brineand dried over sodium sulfate. After filtering and concentration underreduced pressure, the resulting residues were purified by silica gelcolumn chromatography (methanol/dichloromethane) to obtain the targetcompound (0.7 mg, 3%).

LCMS: m/z 527 [M+H]⁺

HPLC retention time: 2.93 min (analysis condition D)

Example 634 Compound T13-44-[2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-acetyl]-piperazine-1-carboxylic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundA9-10, the title compound was prepared from Compound T13-2 and1-(tert-butoxy carbonyl)piperazine.

LCMS: m/z 582 [M+H]⁺

HPLC retention time: 2.32 min (analysis condition D)

Example 635 Compound T13-53-Bromo-6,6-dimethyl-8-(2-oxo-2-piperazin-1-yl-ethoxy)-5,6-dihydro-benzo[b]carbazol-11-oneHydrochloric Acid Salt

According to the same method as the method for synthesizing CompoundA8-1, the title compound was prepared from Compound T13-4.

LCMS: m/z 482 [M+H]⁺

HPLC retention time: 1.75 min (analysis condition D)

Example 636 Compound T13-63-Bromo-8-[2-(4-methanesulfonyl-piperazin-1-yl)-2-oxo-ethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T13-5 andmethanesulfonyl chloride.

LCMS: m/z 560 [M+H]⁺

HPLC retention time: 2.00 min (analysis condition D)

Example 637 Compound T13-73-Bromo-6,6-dimethyl-8-{2-oxo-2-[4-(propane-2-sulfonyl)-piperazin-1-yl]-ethoxy}-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T13-5 andisopropylsulfonyl chloride.

LCMS: m/z 588 [M+H]⁺

HPLC retention time: 2.47 min (analysis condition D)

Example 638 Compound T13-88-[2-(4-Acetyl-piperazin-1-yl)-2-oxo-ethoxy]-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T13-5 and aceticanhydride.

LCMS: m/z 524 [M+H]⁺

HPLC retention time: 1.85 min (analysis condition D)

Example 639 Compound T13-93-Bromo-6,6-dimethyl-8-[2-(4-oxetan-3-yl-piperazin-1-yl)-2-oxo-ethoxy]-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundB3-32, the title compound was prepared from Compound T13-5 and3-oxetanone.

LCMS: m/z 538 [M+H]⁺

HPLC retention time: 1.88 min (analysis condition D)

Example 640 Compound T13-104-[2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl-oxy)-acetyl]-piperazine-1-sulfonicAcid Methylamide

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T13-5 and2-oxo-oxazolidine-3-sulfonic acid methylamide.

LCMS: m/z 575 [M+H]⁺

HPLC retention time: 2.29 min (analysis condition A)

Example 641 Compound T14-14-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxymethyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 and1-(tert-butoxy carbonyl)-4- (hydroxy methyl)piperidine.

LCMS: m/z 553 [M+H]⁺

HPLC retention time: 2.80 mm (analysis condition D)

Example 642 Compound T14-23-Bromo-6,6-dimethyl-8-(pipendin-4-ylmethoxy)-5.6-dihydro-benzo-[b]carbazol-11-onehydrochlonc acid salt

According to the same method as the method for synthesizing CompoundA8-1, the title compound was prepared from Compound T14-1.

LCMS: m/z 454 [M+H]⁺

HPLC retention time: 1.90 min (analysis condition D)

Example 643 Compound T14-33-Bromo-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-ylmethoxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundB3-32, the title compound was prepared from Compound T14-2 and3-oxetanone.

¹H-NMR (400 MHz, CDCl₃) δ: 9.24 (1H, s), 8.37 (1H, d, 8.8 Hz), 8.30 (1H,d, 8.3 Hz), 7.57 (1H, d, 1.5 Hz), 7.41 (1H, dd, 8.3, 1.5 Hz), 7.08 (1H,d, 2.4 Hz), 6.98 (1H, dd, 8.8, 2.4 Hz) 4.60-4.95 (7H, m), 3.93 (2H, d,5.9 Hz), 3.50 (1H, m), 2.83 (2H, d, 11.2 Hz), 1.89 (4H, m), 1.78 (6H,s),

LCMS: m/z 509 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition A)

Example 644 Compound T14-48-(1-Acetyl-piperidin-4-ylmethoxy)-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T14-2 and aceticanhydride.

LCMS: m/z 495 [M+H]⁺

HPLC retention time: 2.53 min (analysis condition A)

Example 645 Compound T14-53-Bromo-8-(1-methanesulfonyl-piperidin-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T14-2 andmethanesulfonyl chloride.

LCMS: m/z 531 [M+H]⁺

HPLC retention time: 2.30 min (analysis condition D)

Example 646 Compound T14-63-Bromo-6,6-dimethyl-8-[1-(propane-2-sulfonyl)-piperidin-4-ylmethoxy]-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T14-2 andisopropylsulfonyl chloride.

LCMS: m/z 559 [M+H]⁺

HPLC retention time: 2.58 min (analysis condition D)

Example 647 Compound T14-73-[4-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxymethyl)-piperidin-1-yl]-azetidine-1-carboxylic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundB3-32, the title compound was prepared from Compound T14-2 and3-oxo-azetidine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 608 [M+H]⁺

HPLC retention time: 2.29 min (analysis condition A)

Example 648 Compound T14-88-(1-Azetidin-3-yl-piperidin-4-ylmethoxy)-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA8-1, the title compound was prepared from Compound T14-7.

LCMS: m/z 508 [M+H]⁺

HPLC retention time: 1.90 min (analysis condition A)

Example 649 Compound T14-93-Bromo-8-[1-(1-methanesulfonyl-azetidin-3-yl)-piperidin-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T14-8 and mesylchloride.

LCMS: m/z 586 [M+H]⁺

HPLC retention time: 2.06 min (analysis condition A)

Example 650 Compound T14-108-[1-(1-Acetyl-azetidin-3-yl)-piperidin-4-ylmethoxy]-3-bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T14-8 and aceticanhydride.

LCMS: m/z 550 [M+H]⁺

HPLC retention time: 2.53 min (analysis condition A)

Example 651 Compound T15-14-[2-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-ethyl]-piperidine-1-carboxylic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 andN-(tert-butoxycarbonyl)-4-piperidine ethanol.

LCMS: m/z 567 [M+H]⁺

HPLC retention time: 2.29 min (analysis condition D)

Example 652 Compound T15-23-Bromo-6,6-dimethyl-8-(2-piperidin-4-yl-ethoxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA8-1, the title compound was prepared from Compound T15-1.

LCMS: m/z 467 [M+H]⁺

HPLC retention time: 1.95 min (analysis condition D)

Example 653 Compound T15-33-Bromo-6,6-dimethyl-8-[2-(1-oxetan-3-yl-piperidin-4-yl)-ethoxy]-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundB3-32, the title compound was prepared from Compound T15-2 and3-oxetanone.

LCMS: m/z 523 [M+H]⁺

HPLC retention time: 2.28 min (analysis condition D)

Example 654 Compound T16-14-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxy)-1-oxa-8-aza-spiro[4.5]decane-8-carboxylic Acid Tert-Butyl Ester

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A5-1 and3-hydroxy-1-oxa-8-aza-spiro[4.5] decane-8-carboxylic acid tert-butylester.

LCMS: m/z 595 [M+H]⁺

HPLC retention time: 3.08 min (analysis condition A)

Example 655 Compound T16-23-Bromo-6,6-dimethyl-8-(1-oxa-8-aza-spiro[4.5]decan-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA8-1, the title compound was prepared from Compound T16-1.

LCMS: m/z 496 [M+H]⁺

HPLC retention time: 1.99 min (analysis condition A)

Example 656 Compound T16-33-Bromo-8-(8-methanesulfonyl-1-oxa-8-aza-spiro[4.5]decan-4-yloxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA9-1, the title compound was prepared from Compound T16-2 and mesylchloride.

LCMS: m/z 573 [M+H]⁺

HPLC retention time: 2.56 min (analysis condition A)

Example 657 Compound T16-43-Bromo-6,6-dimethyl-8-(8-oxetan-3-yl-1-oxa-8-aza-spiro[4.5]decan-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundB3-32, the title compound was prepared from Compound T16-2 and3-oxetanone.

LCMS: m/z 551 [M+H]⁺

HPLC retention time: 2.01 min (analysis condition A)

Example 658 Compound T17-13,7,9-Tribromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere,4-[1,3]dithian-2-ylidene-piperidine-1-carboxylic acid tert-butyl ester(100 g, 0.332 mmol) was dissolved in dichloromethane (2.50 mL), addedwith trifluoromethanesulfonic acid (30.8 μL, 0.348 mmol) at −20° C., andstirred at room temperature for 30 min. The reaction solution was cooledto −70° C., and then added dropwise with the dichloromethane (2.50 mL)solution of3-bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound A5-1, 177 mg, 0.498 mmol) and triethylamine (78.6 μL, 0.564mmol). Thereafter, triethylamine hydrotrifluoric acid salt (262 μL,1.610 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (460 mg, 1.610 mmol)were added thereto and stirred at −70° C. for 1 hr. The reactionsolution was added to aqueous solution of sodium hydroxide (1 M),extracted with ethyl acetate, washed with water, saturated aqueoussolution of sodium bicarbonate, saturated brine and dried over sodiumsulfate. After filtering and concentration under reduced pressure, theresulting residues were purified by silica gel column chromatography(ethyl acetate/hexane) and aminosilica gel column chromatography (ethylacetate/hexane) to obtain the target compound (42.0 mg, 25%).

LCMS: m/z 511 [M+H]⁺

HPLC retention time: 6.34 min (analysis condition B)

Example 659 Compound T17-23,7,9-Tribromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-1, the title compound was prepared from Compound A17-1 and(S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol.

LCMS: m/z 625 [M+H]⁺

HPLC retention time: 3.41 min (analysis condition A)

Example 660 Compound T17-33,7,9-Tribromo-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

According to the same method as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound T17-2.

LCMS: m/z 585 [M+H]⁺

HPLC retention time: 2.44 min (analysis condition A)

Example 661 Compound T18-13-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound A5-1, 18.0 mg, 50.5 μmol) was dissolved in DMF (0.18 mL),added with toluene-4-sulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (14.5 mg, 0.0505 mmol) and potassium carbonate (10.0 mg,0.07575 mmol), and the mixture was stirred at 70° C. for 3 days. Thereaction solution was added to water, extracted with ethyl acetate, andthe organic layer was dried over magnesium sulfate. The residuesobtained after concentration under reduced pressure were purified bypreparative TLC (methylene chloride/methanol) to obtain the titlecompound (16.6 mg, 70%).

LCMS: m/z 470 [M+H]⁺

HPLC retention time: 3.01 min (analysis condition F)

Example 662 Compound T18-23-Bromo-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound T18-1.

LCMS: m/z 430 [M+H]⁺

HPLC retention time: 4.72 min (analysis condition H)

Example 663 Compound T19-1-13-Bromo-8-methoxy-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A10-1,the title compound was prepared from Compound A4.

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 2.84 min (analysis condition D)

Example 664 Compound T19-13-Bromo-8-hydroxy-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound T19-1-1.

LCMS: m/z 370 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition D)

Example 665 Compound T19-23-Bromo-8-(2-diethylaminoethoxy)-6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound A5-1 (9.8 mg, 36%).

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 1.96 min (analysis condition D)

Example 666 Compound T19-33-Bromo-8-(2-diethylaminoethoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound T19-1.

LCMS: m/z 469 [M+H]⁺

HPLC retention time: 2.09 min (analysis condition D)

Example 667 Compound T205-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-pentanoic Acid

Under the same conditions as the method for synthesizing Compound A7-17,Compound A5-1 and methyl 5-bromovalerate were reacted, added with 1 NNaOH (140 L), and then stirred at room temperature for 2 hr. Thereaction mixture was added with 2 N HCl (70 μL), and concentrated underreduced pressure. The resulting residues were purified by preparativeTLC (methylene chloride:methanol=15:1) to obtain 7 mg (55%).

LCMS: m/z 456 [M+H]⁺

HPLC retention time: 5.88 min (analysis condition H)

Example 668 Compound T21(R)-5-(3-Bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-4-hydroxy-pentanoic Acid

Under the same conditions as the method for synthesizing Compound T20,the title compound was prepared from the reaction between Compound A5-1and toluene-4-sulfonic acid (R)-5-oxo-tetrahydrofuran-2-yl methyl ester.

LCMS: m/z 471 [M+H]⁺

HPLC retention time: 4.57 min (analysis condition H)

Example 669 Compound T22-0[5-(Tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol

To THF (50 mL), NaH (1.41 g, 0.032 mmol) was added at room temperature,followed by addition of((4R,5R)-5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5.0g, 0.031 mmol) at room temperature. The mixture was stirred at roomtemperature for 1 hr. After that, TBSCl (5.11 g, 0.034 mmol) was addedat room temperature and stirred at room temperature overnight. Thereaction solution was added with saturated aqueous solution of sodiumhydrogen carbonate and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate. The residues obtained afterconcentration under reduced pressure were purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (8.21g, 96%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 3.64-4.98 (6H, m), 2.37 (1H, m), 1.41 (3H,s), 1.40 (3H, s), 0.90 (9H, s), 0.08 (6H, s)

Example 670 Compound T22-13-Bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound A5-1 and[5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol(Compound T22-0) (704 mg, 80%).

LCMS: m/z 614 [M+H]⁺

HPLC retention time: 4.00 min (analysis condition F)

Example 671 Compound T22-1-13-Bromo-8-((1R,5R)-5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the DMF (0.4 mL) suspension of3-bromo-8-[(1R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundT22-1, 50.3 mg, 0.0818 mmol) and copper (I) iodide (34 mg), sodiummethoxide (1 M methanol solution, 0.82 mL, 0.818 mmol) was added and themixture was stirred for 6 hr and 45 min at ambient temperature of 90° C.After cooling to room temperature, the reaction mixture was added withdiethyl ether and ethyl acetate, and the insoluble matters were removedby Celite filtration. The concentrated residues were added with diethylether, hexane, ethyl acetate and water, and then the mixture wasextracted twice with diethyl ether. The organic layer was washed withwater and subsequently with brine, dried over sodium sulfate andconcentrated under reduced pressure. The resulting crude product waspurified by preparative TLC (Merck60 F₂₅₄, 0.5 mm) {solution forelution: hexane/ethyl acetate (1:2)} to obtain the title compound(colorless oily substance, 22.6 mg, 55%).

¹H-NMR (270 MHz, CDCl₃) δ: 8.44-8.38 (1H, b), 8.39 (1H, d, 8.6 Hz), 8.31(1H, d, 8.2 Hz), 7.60 (1H, d, 1.3 Hz), 7.44 (1H, dd, 8.2 Hz, 1.3 Hz),7.12 (1H, d, 2.3 Hz), 7.02 (1H, dd, 8.6 Hz, 2.3 Hz), 4.41-4.10 (4H, m),4.00-3.88 (1H, m), 3.86-3.76 (1H, m), 1.78 (6H, s), 1.50 (3H, s), 1.49(3H, s)

LCMS: m/z 500 [M+H]⁺

HPLC retention time: 2.85 min (analysis condition C)

Example 672 Compound T22-1-2 Acetic acid(3R,4R)-5-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxymethyl)-2,2-dimethyl[1,3]dioxolan-4-yl methyl Ester

The title compound was obtained as a by-product of the synthesis ofT22-1-1 (white solid, 17.8 mg, 40%).

¹H-NMR (270 MHz, CDCl₃) δ: 8.92-8.80 (1H, b), 8.40 (1H, d, 8.9 Hz), 8.31(1H, d, 8.6 Hz), 7.58 (1H, d, 1.7 Hz), 7.43 (1H, dd, 8.6 Hz, 1.7 Hz),7.14 (1H, d, 2.3 Hz), 7.02 (1H, dd, 8.9 Hz, 2.3 Hz), 4.51-4.38 (1H, m),4.34-4.16 (4H, m), 2.13 (3H, s), 1.78 (6H, s), 1.50 (6H, s)

LCMS: m/z 542 [M+H]⁺

HPLC retention time: 3.00 min (analysis condition C)

Example 673 Compound T22-23-Bromo-6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound T22-1 (2.83 g,95%).

LCMS: m/z 460 [M+H]⁺

HPLC retention time: 4.50 min (analysis condition H)

Example 674 Compound T22-33-Bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound B3-4,the title compound was prepared from Compound T22-1.

LCMS: m/z 628 [M+H]⁺

HPLC retention time: 4.74 min (analysis condition F)

Example 675 Compound T22-43-Bromo-8-((2R,3R)-2,3-dihydroxy-pentyloxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound T22-3.

LCMS: m/z 475 [M+H]⁺

HPLC retention time: 4.86 min (analysis condition H)

Example 676 Compound T22-5{3-Bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]carbazol-5-yl}-aceticAcid Methyl Ester

Under nitrogen atmosphere,3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundT22-1, 40.0 mg, 65.2 μmol) was dissolved in DMF (0.20 mL), added at 0°C. with methyl bromoacetate (30.5 μL, 134.5 μmol) and sodium hydride(4.5 mg, 132 μmol), and then stirred at room temperature for 2 hr. Theresidues obtained from the reaction solution after concentration underreduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (44.5 mg, 85%).

LCMS: m/z 686 [M+H]⁺

HPLC retention time: 3.35 min (analysis condition D)

Example 677 Compound T22-6{3-Bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]carbazol-5-yl}-aceticAcid

{3-Bromo-8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]carbazol-5-yl}-aceticacid methyl ester (Compound T22-5, 40 mg, 60.0 μmol) was dissolved inthe mixture solvent of methanol (120 μl) and water (30 μl), added withlithium hydroxide monohydrate (10 mg, 240 μmol), and then stirred 40° C.for 15 min. The residues obtained from the reaction solution afterconcentration under reduced pressure were purified by silica gel columnchromatography (methylene chloride/methanol) to obtain the targetcompound (35.2 mg, 96%).

LCMS: m/z 672 [M+H]⁺

HPLC retention time: 3.41 min (analysis condition D)

Example 678 Compound T22-7[3-Bromo-6,6-dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-benzo[b]carbazol-5-yl]-aceticAcid

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound T22-6 (6.2 mg,31%).

LCMS: m/z 518 [M+H]⁺

HPLC retention time: 1.30 min (analysis condition D)

Example 679 Compound T22-8[3-Bromo-6,6-dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-benzo[b]carbazol-5-yl]-aceticAcid Methyl Ester

[3-Bromo-6,6-dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-benzo[b]carbazol-5-yl]-aceticacid (Compound T22-6, 15.0 mg, 29.0 μmol) was dissolved in methanol(0.30 mL), added with trimethylsilyldiazomethane (0.10 mL), and thenstirred at room temperature for 1 hr. The residues obtained from thereaction solution after concentration under reduced pressure werepurified by silica gel column chromatography (methylenechloride/methanol) to obtain the target compound (15.2 mg, 96%).

LCMS: m/z 532 [M+H]⁺

HPLC retention time: 1.80 min (analysis condition D)

Example 680 Compound T23-13-Bromo-5-((R)-1,2-dihydroxyethyl)-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound T18-1and Compound T18-2, the title compound was prepared from Compound A5-1and toluene-4-sulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-yl methylester.

LCMS: m/z 366 [M+H]⁺

HPLC retention time: 4.50 min (analysis condition H)

Example 681 Compound T23-23-Bromo-5-((S)-1,2-dihydroxyethyl)-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound T18-1and Compound T18-2, the title compound was prepared from Compound A4 andtoluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-yl methylester.

LCMS: m/z 366 [M+H]⁺

HPLC retention time: 4.50 min (analysis condition H)

Example 682 Compound T24-13-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the DMF (1 mL) suspension of3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundT18-1, 112.2 mg, 0.239 mmol) and sodium hydride (60%) (19 mg, 0.477mmol), cooled in an ice bath, methyl iodide (37 mL, 0.596 mmol) wasadded. The reaction mixture was stirred at room temperature for 45 min,and then added with saturated aqueous solution of ammonium chloride andsaturated aqueous solution of sodium thiosulfate under ice cooling. Themixture was extracted twice with ethyl acetate/diethyl ether/hexane. Theorganic layer was washed with water and subsequently with aqueoussolution of ammonium chloride, dried over sodium sulfate, and thenconcentrated under reduced pressure. The resulting crude product waspurified by flash column chromatography {Merck Kieselgel60, solution forelution: hexane/ethyl acetate (1:1)} to obtain the title compound (whitesolid, 107.3 mg, 93%).

¹H-NMR (270 MHz, CDCl₃) δ: 8.41 (1H, d, 8.6 Hz), 8.35 (1H, d, 8.9 Hz),7.56 (1H, d, 1.7 Hz), 7.46 (1H, dd, 8.6 Hz, 1.7 Hz), 7.14 (1H, d, 2.3Hz), 7.00 (1H, dd, 8.9 Hz, 2.3 Hz), 4.60-4.49 (1H, m), 4.20-3.90 (4H,m), 4.03 (3H, s), 1.88 (6H, s), 1.50 (3H, s), 1.43 (3H, s)

LCMS: m/z 484 [M+H]⁺

HPLC retention time: 6.59 min (analysis condition B)

Example 683 Compound T24-23-Bromo-8-((R)-2,3-dihydroxy-propoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the THF (0.15 mL)-MeOH (0.1 mL) solutionof 3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundT24-1, 15.5 mg, 0.0320 mmol), 0.5 M aqueous solution of sulfuric acid(128 μL, 0.0640 mmol) was added at room temperature. The reactionmixture was stirred at ambient temperature of 55° C. for 2 hr, cooled toroom temperature, and then added with diethyl ether and subsequentlywith sodium hydrogen carbonate (11 mg). The mixture was extracted twicewith diethyl ether/ethyl acetate, and the organic layer was washed withbrine, dried over sodium sulfate and concentrated under reduced pressureto obtain the title compound (white solid, 11.9 mg, 84%).

¹H-NMR (270 MHz, CD₃OD) δ: 8.26 (1H, d, 8.6 Hz), 8.20 (1H, d, 8.9 Hz),7.77 (1H, d, 1.7 Hz), 7.42 (1H, dd, 8.6 Hz, 1.7 Hz), 7.33 (1H, d, 2.3Hz), 7.09 (1H, dd, 8.9 Hz, 2.3 Hz), 4.26-3.96 (3H, m), 4.10 (3H, s),3.74-3.66 (1H, m), 1.92 (6H, s)

LCMS: m/z 444 [M+H]⁺

HPLC retention time: 4.65 min (analysis condition B)

Example 684 Compound T253-Bromo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A3-1and Compound A4, the title compound was prepared from3,4-dihydro-1H-naphthalen-2-one (560 mg).

LCMS: m/z 340 [M+H]⁺

HPLC retention time: 4.57 min (analysis condition H)

Example 685 Compound T26-18-[(4R,5R)-5-(Tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-iodo-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere,3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (CompoundT22-1, 300 mg, 0.47 mmol), sodium iodide (147 mg, 0.94 mmol) and copperiodide (9.40 mg, 0.047 mmol) were dissolved in dioxane (1.00 ml), addedwith (1R,2R)—N,N,N′,N′-tetramethyl-cyclohexane-1,2-diamine (15.4 μl,0.094 mmol), and then stirred at 110° C. for 16 hr. The residuesobtained from the reaction solution after concentration under reducedpressure were purified by silica gel column chromatography (methylenechloride/methanol) to obtain the title compound (220 mg, 70%).

LCMS: m/z 662 [M+H]⁺

HPLC retention time: 3.40 min (analysis condition D)

Example 686 Compound T26-23-Iodo-6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound T26-1 (17.0 mg,90%).

LCMS: m/z 508 [M+H]⁺

HPLC retention time: 1.77 min (analysis condition D)

Example 687 Compound T27-13-Bromo-9-(2-fluoro-4-methoxy-phenyl)-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

To the mixture of6-bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (CompoundE1, 410 mg, 1.44 mmol), tetrakistriphenylphosphine palladium (80 mg,0.05 eq.) and sodium carbonate (614 mg, 4 eq.), toluene (3 mL) and water(1 ml) were added and then stirred at room temperature and at 90° C. for3 hr. The mixture was extracted by adding water and diethyl ether, andthe organic layer was washed with brine, and dried over magnesiumsulfate. The residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/hexane) to obtain6-(2-fluoro-4-methoxy-phenyl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(white solid, 320 mg).

Thus-obtained6-(2-fluoro-4-methoxy-phenyl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(320 mg, 0.1 mmol) and 3-bromophenylhydrazine (0.29 g, 1.3 eq.) weredissolved in acetic acid (1 mL), and stirred under nitrogen atmosphereat 90° C. for 8 hr. After cooling, the reaction solution was added withethyl acetate, washed with water, saturated aqueous solution of sodiumhydrogen carbonate, and saturated brine, dried over magnesium sulfate,and then filtered. The residues obtained after concentration underreduced pressure were dissolved in THF (3 mL) comprising 10% water,added with DDQ (227 mg, 3 eq.) at room temperature, and stirred at roomtemperature for 2 hr. To the reaction solution, the mixture solution ofTHF/diethyl ether (1:1) was added, and the reaction solution was washedwith 0.5 N aqueous solution of sodium hydroxide and saturated brine,dried over sodium sulfate, and then filtered. The residues obtainedafter concentration under reduced pressure were purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain the titlecompound (red solid, 75 mg).

LCMS: m/z 494, 496 [M+H]⁺

HPLC retention time: 3.10 min (analysis condition C)

Example 688 Compound T27-23-Bromo-9-(2-fluoro-4-hydroxy-phenyl)-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound T27-1.

LCMS: m/z 464, 466 [M+H]⁺

HPLC retention time: 2.68 min (analysis condition C)

Example 689 Compound U54-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

2-Bromo-3-nitro-benzonitrile (Compound U1, 678 mg, 2.987 mmol) wasdissolved in ethanol (20.9 mL) and water (8.96 mL), added with aceticacid (2.39 mL, 41.81 mmol) and iron (1.17 g, 20.91 mmol), and stirred at60° C. for 18 hr. The reaction solution was poured into aqueous solutionof sodium hydroxide (1 M), extracted with ethyl acetate, washed withwater and saturated brine, dried over sodium sulfate, and then filtered.After concentration under reduced pressure, 3-amino-2-bromo-benzonitrile(Compound U2) was obtained as a crude product.

The crude product obtained from the above was dissolved in 12 M aqueoussolution of hydrochloric acid (4.00 mL), added slowly at 0° C. withaqueous solution in which sodium nitrite (247 mg, 3.584 mmol) isdissolved in water (3.58 mL), and then the mixture was stirred at 0° C.for 30 min. Under light-shielding conditions, aqueous solution in whichtin chloride dihydrate (2.02 g, 8.961 mmol) is dissolved in 12 M aqueoussolution of hydrochloric acid (4.00 mL) was slowly added to the reactionsolution at 0° C., and then the mixture was stirred at 0° C. for 1 hr.The reaction solution was poured into 5 M aqueous solution of sodiumhydroxide, extracted with ethyl acetate, washed with saturated brine,dried over sodium sulfate, and filtered. After concentration underreduced pressure, 2-bromo-3-hydrazino-benzonitrile (Compound U3) wasobtained as a crude product. Under nitrogen atmosphere, the above crudeproduct and 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(Compound A2, 462 mg, 2.260 mmol) were added with TFA (6.78 mL) andstirred at 100° C. for 2 hr. After cooling, the reaction solution waspoured into saturated aqueous solution of sodium bicarbonate, extractedwith ethyl acetate, washed with water and saturated brine, dried oversodium sulfate, and filtered. After concentration under reducedpressure,4-bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U4) was obtained as a crude product. The above crude productwas dissolved in THF (10.0 mL) and water (1.00 mL), added with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.54 g, 6.780 mmol), andstirred at room temperature for 20 hr. The reaction solution was pouredinto 1 M aqueous solution of sodium hydroxide, extracted withcyclopentylmethyl ether, washed with 1 M aqueous solution of sodiumhydroxide, water and saturated brine, dried over sodium sulfate, andfiltered. The residues obtained after concentration under reducedpressure were washed with cyclopentylmethyl ether to obtain the titlecompound (460 mg, 52%).

LCMS: m/z 395 [M+H]⁺

HPLC retention time: 2.25 min (analysis condition D)

Example 690 Compound U68-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

4-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U5, 325 mg, 0.822 mmol) was added with pyridine hydrochloridesalt (3.80 g, 32.89 mmol) and stirred at 160° C. for 28 hr. The reactionsolution was poured into water, extracted with ethyl acetate, washedwith water, dried over sodium sulfate, and filtered. After concentrationunder reduced pressure, the title compound was obtained as a crudeproduct.

LCMS: m/z 381 [M+H]⁺

HPLC retention time: 1.92 min (analysis condition D)

Example 691 Compound U7-1 4-Bromo-8-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from the reaction between Compound U6and (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (354 mg, 87%).

LCMS: m/z 495 [M+H]⁺

HPLC retention time: 2.35 min (analysis condition D)

Example 692 Compound U7-24-Bromo-8-((S)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound U7-1.

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition C)

Example 693 Compound U8-28-((R)-2,3-Dihydroxy-propoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound U7-1and Compound U7-2, the title compound was prepared from the reactionbetween Compound U6 and (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol(4.5 mg, 29%).

LCMS: m/z 455 [M+H]⁺

HPLC retention time: 2.37 min (analysis condition C)

Example 694 Compound U8-3-1 8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3,4-dicarbonitrile

Under nitrogen atmosphere,4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U6, 20.0 mg, 40.37 μmol) was dissolved in DMA (0.35 mL), addedwith copper (I) cyanide (18.1 mg, 201.9 μmol), and stirred at 200° C.for 1 hr under irradiation with microwave. The reaction solution waspoured into water, extracted with ethyl acetate, washed with water andsaturated brine, dried over sodium sulfate, and then filtered. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound as a crude product.

LCMS: m/z 442 [M+H]⁺

HPLC retention time: 2.30 min (analysis condition D)

Example 695 Compound U8-3-28-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3,4-dicarbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound U8-3-1 (9.5 mg,59%).

LCMS: m/z 402 [M+H]⁺

HPLC retention time: 2.40 min (analysis condition D)

Example 696 Compound U8-4-1 8-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-4-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound U9,the title compound was prepared as a crude product from Compound U8-1(9.5 mg, 59%).

LCMS: m/z 433 [M+H]⁺

HPLC retention time: 2.34 min (analysis condition A)

Example 697 Compound U8-4-28-((R)-2,3-Dihydroxy-propoxy)-4-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound U8-4-1 (crudeproduct) (9.7 mg, 52%).

LCMS: m/z 393 [M+H]⁺

HPLC retention time: 1.69 min (analysis condition A)

Example 698 Compound U8-4-38-((R)-2,3-Dihydroxy-propoxy)-4-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere,8-((R)-2,3-dihydroxy-propoxy)-4-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U8-4-2, 8.0 mg, 20.39 μmol) was dissolved in methanol (2.0 mL)and chloroform (2.00 mL), added with trimethylsilyldiazomethane (diethylether solution, 2 M, 15.3 μL, 30.58 μmol) and diisopropylethylamine(0.05 mL), and then stirred at room temperature for 31 hr. The residuesobtained from the reaction solution after concentration under reducedpressure were purified by silica gel column chromatography(methanol/dichloromethane) to obtain the title compound (5.1 mg, 62%).

LCMS: m/z 407 [M+H]⁺

HPLC retention time: 3.74 min (analysis condition A)

Example 699 Compound U8-5-1 8-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-4-trifluoromethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere,4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U8-1, 25.0 mg, 50.47 μmol) was dissolved in DMF (0.75 mL),added with copper iodide (I) (48.0 mg, 252.3 μmol) anddifluoro-fluorosulfonyl-acetic acid methyl ester (31.9 μL, 252.3 μmol),and then stirred at 100° C. for 2 days. The reaction solution was pouredinto hydrochloric acid (1 M), extracted with ethyl acetate, washed withwater, saturated aqueous solution of sodium bicarbonate and saturatedbrine, dried over sodium sulfate, and then filtered. The residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound as a crude product.

LCMS: m/z 485 [M+H]⁺

HPLC retention time: 2.88 min (analysis condition A)

Example 700 Compound U8-5-28-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-4-trifluoromethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound U8-5-1 (4.0 mg,30%).

LCMS: m/z 445 [M+H]⁺

HPLC retention time: 2.17 min (analysis condition A)

Example 701 Compound U8-6-14-Cyclopropyl-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere,2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (13.2 mg, 78.73μmol) and potassium phosphate (212.27 mg, 212.0 μmol) were dissolved inwater (0.20 mL), and the mixture was stirred at room temperature for 15min. To the reaction solution,4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U8-1, 30.0 mg, 60.56 μmol), palladium acetate (1.36 mg, 6.056μmol), and tricyclohexylphosphine (toluene solution, 20 wt %, 17.0 mg,12.11 μmol) were added and the mixture was stirred at 80° C. for 24 hr.The reaction solution was poured into hydrochloric acid (1 M), extractedwith ethyl acetate, washed with saturated aqueous solution of sodiumbicarbonate and saturated brine, dried over sodium sulfate, and thenfiltered. The residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (13.6 mg, 49%).

LCMS: m/z 457 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition D)

Example 702 Compound U8-6-24-Cyclopropyl-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound U8-6-1.

LCMS: m/z 417 [M+H]⁺

HPLC retention time: 2.42 min (analysis condition A)

Example 703 Compound U8-7-1(S)-8-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-4,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere,4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U8-1, 30.0 mg, 60.56 μmol) and lithium chloride (7.70 mg,181.7 μmol) were dissolved in DMF (1.00 mL), added with tetramethyl tin(12.5 μL, 90.84 μmol), tetrakistriphenylphosphine palladium (3.50 mg,6.056 μmol) and tricyclohexylphosphine (toluene solution, 20 wt %, 17.0mg, 3.028 μmol), and the mixture was stirred at 100° C. for 24 hr. Thereaction solution was poured into hydrochloric acid (1 M), extractedwith ethyl acetate, washed with water, saturated aqueous solution ofsodium bicarbonate and saturated brine, dried over sodium sulfate, andthen filtered. The residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/hexane) to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-4,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrileas a crude product (20.9 mg, 80%).

Example 704 Compound U8-7-28-((R)-2,3-Dihydroxy-propoxy)-4,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound U8-7-1.

LCMS: m/z 391 [M+H]⁺

HPLC retention time: 1.82 min (analysis condition A)

Example 705 Compound U8-8-13-Cyano-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-4-carboxylicAcid Amide

Under nitrogen atmosphere,4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U8-1, 30.0 mg, 60.56 μmol), palladium acetate (1.36 mg, 6.056μmol), 1,1′-bis(diphenylphosphino)ferrocene (3.36 mg, 6.056 μmol),imidazole (4.12 mg, 60.56 μmol) and tert-potassium butoxy (10.2 mg,90.84 μmol) were dissolved in formamide (3.00 mL) and the mixture wasstirred at 180° C. for 5 min under irradiation with microwave. Thereaction solution was poured into water, extracted with ethyl acetate,washed with water and saturated brine, dried over sodium sulfate, andthen filtered. The residues obtained after concentration under reducedpressure were purified by silica gel column chromatography(methanol/dichloromethane) to obtain the target compound (7.6 mg, 27%).

LCMS: m/z 460 [M+H]⁺

HPLC retention time: 1.82 min (analysis condition A)

Example 706 Compound U8-8-23-Cyano-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-4-carboxylicAcid

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound U8-8-1.

LCMS: m/z 421 [M+H]⁺

HPLC retention time: 1.57 min (analysis condition A)

Example 707 Compound U8-8-33-Cyano-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-4-carboxylicAcid Amide

The title compound was obtained as a by-product of the synthesis ofCompound U8-8-2.

LCMS: m/z 420 [M+H]⁺

HPLC retention time: 1.27 min (analysis condition A)

Example 708 Compound U94-Hydroxy-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere,4-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U5, 10.0 mg, 25.30 μmol), X-phos (1.07 mg, 2.530 μmol), sodiumhydroxide (4.36 mg, 75.90 μmol) and Pd₂dba₃.CHCl₃ (1.31 mg, 1.265 μmol)were dissolved in dioxane (0.50 mL) and water (0.50 mL) and the mixturewas stirred at 100° C. for 1 hr. The reaction solution was poured intohydrochloric acid (1 M), extracted with ethyl acetate, washed withsaturated brine, dried over sodium sulfate, and then filtered. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) andwashed with dichloromethane to obtain the title compound (5.4 mg, 64%).

LCMS: m/z 333 [M+H]⁺

HPLC retention time: 1.62 min (analysis condition D)

Example 709 Compound U10-14-((R)-2,3-Dihydroxy-propoxy)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from the reaction between Compound U9and (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol.

LCMS: m/z 407 [M+H]⁺

HPLC retention time: 2.06 min (analysis condition A)

Example 710 Compound U10-24-((S)-2,3-Dihydroxy-propoxy)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from the reaction between Compound U9and (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol.

LCMS: m/z 407 [M+H]⁺

HPLC retention time: 2.06 min (analysis condition A)

Example 711 Compound U114-Amino-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere,4-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound U5, 25.0 mg, 63.25 μmol), copper iodide (2.41 mg, 12.65 μmol),sodium azide (20.6 mg, 316.3 μmol),(1S,2S)—N,N′-dimethyl-cyclohexane-1,2-diamine (2.70 mg, 18.98 μmol), andsodium ascorbate (1.25 mg, 6.325 μmol) were dissolved in ethanol (0.70mL) and water (0.30 mL) and the mixture was stirred at 100° C. for 2 hr.The reaction solution was poured into aqueous solution of sodiumhydroxide (1 M), extracted with ethyl acetate, washed with water andsaturated brine, dried over sodium sulfate, and then filtered. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (methanol/dichloromethane)to obtain the title compound (5.6 mg, 27%).

LCMS: m/z 332 [M+H]⁺

HPLC retention time: 2.16 min (analysis condition A)

Example 712 Compound V23-Fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole

Under nitrogen atmosphere, the acetic acid (1 mL) suspension of7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,101.0 mg, 0.495 mmol) and (3-fluoro-phenyl)-hydrazine hydrochloric acidsalt (Compound VI, 96.5 mg, 0.593 mmol) was stirred at ambienttemperature of 95° C. for 3.75 hr. After cooling to room temperature,the reaction mixture was added with water (1 mL) and hexane/ethylacetate (15:1) (0.5 mL), and stirred at room temperature for 15 min. Thesolid was filtered, washed with hexane/ethyl acetate (15:1), and thendried under reduced pressure to obtain the title compound (beige powder,72.7 mg, 50%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.92-7.82 (1H, b), 7.47 (1H, dd, 8.9 Hz, 5.6Hz), 7.10-7.03 (2H, m), 6.95-6.81 (2H, m), 4.05 (2H, s), 3.86 (3H, s),1.67 (6H, s)

Example 713 Compound V33-Fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the THF (1.8 mL)-water (0.18 mL) solutionof 3-fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole(Compound V2, 72.4 mg, 0.245 mmol), DDQ (122.4 mg, 0.539 mmol) was addedand the mixture was stirred at room temperature for 5 hr. The reactionmixture was added with diethyl ether and 0.5 N aqueous solution ofsodium hydroxide (2 mL), and the resulting mixture was extracted twicewith diethyl ether. The organic layer was washed twice with 0.5 Naqueous solution of sodium hydroxide (2 mL) and subsequently twice withbrine (2 mL), and dried over sodium sulfate. After concentration underreduced pressure, hexane/ethyl acetate (5:1) and diethyl ether wereadded to the obtained crude product, and the solid was triturated. Afterremoving the supernatant and drying under reduced pressure, the titlecompound was obtained (yellow solid, 57.0 mg, 75%).

¹H-NMR (270 MHz, CDCl₃) δ: 8.54-8.44 (1H, b), 8.43-8.33 (2H, m),7.16-6.98 (4H, m), 3.93 (3H, s), 1.77 (6H, s)

Example 714 Compound V43-Fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Mixture of3-fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound V3, 56.6 mg, 0.183 mmol) and pyridinium chloride (0.65 g) wasstirred at ambient temperature of 160° C. for 12 hr. The reactionmixture was cooled to room temperature, added with ethyl acetate andwater, and the resulting mixture was extracted four times with ethylacetate. The organic layer was washed with water three times, dried oversodium sulfate, and concentrated under reduced pressure. The obtainedcrude product was used for the next step without further purification(brown solid, 61.6 mg, 100%).

¹H-NMR (270 MHz, CD₃OD) δ: 8.20 (1H, dd, 8.9 Hz, 5.3 Hz), 8.15 (1H, d,9.6 Hz), 7.17 (1H, dd, 9.6 Hz, 2.3 Hz), 7.12 (1H, d, 2.3 Hz), 7.05-6.95(1H, m), 6.88 (1H, dd, 8.9 Hz, 2.3 Hz), 1.74 (6H, s)

Example 715 Compound V5-18-[(1R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the THF (1.5 mL) solution of3-fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound V4, 0.183 mmol),(4S,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl[1,3]dioxolan-4-ol(75.9 mg, 0.275 mmol) and triphenylphosphine (72 mg, 0.275 mmol),toluene solution (125 μL, 0.275 mmol) of DEAD was added dropwise at roomtemperature. The reaction mixture was stirred at ambient temperature of40° C. for 7 hr. After cooling to room temperature, the reaction mixturewas concentrated under reduced pressure, and the resulting crude productwas purified by preparative TLC (Merck 60 F254, 0.5 mm) {solution forelution: hexane/ethyl acetate (3:1)} to obtain the title compound (paleorange amorphous, 54.1 mg, 53.4%).

¹H-NMR (270 MHz, CDCl₃) δ: 8.54-8.45 (1H, b), 8.42-8.33 (2H, m),7.17-6.99 (4H, m), 4.41-4.27 (2H, m), 4.25-4.15 (1H, m), 4.06-3.96 (1H,m), 3.96-3.88 (1H, m), 3.83-3.74 (1H, m), 1.76 (3H, s), 1.75 (3H, s),1.48 (3H, s), 1.47 (3H, s), 0.87 (9H, s), 0.092 (6H, s)

Example 716 Compound V5-23-Fluoro-6,6-dimethyl-8-((3R,4R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the THF (0.3 mL)-MeOH (0.1 mL) solution of8-[(1R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-3-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound V5-1, 52.8 mg, 0.0954 mmol), 0.5 M aqueous solution ofsulfuric acid (0.19 mL, 0.0954 mmol) was added at room temperature. Thereaction mixture was stirred at ambient temperature of 55° C. for 4 hr,cooled to room temperature, and then added with diethyl ether, sodiumhydrogen carbonate (20 mg) and water in order. The mixture was extractedtwice with diethyl ether and subsequently twice with ethyl acetate, andthe organic layer was washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure. The resulting crude product waswashed with dichloromethane, and dried under reduced pressure to obtainthe title compound (white powder, 29.9 mg, 78%).

¹H-NMR (270 MHz, CD₃OD) δ: 8.24 (1H, d, 8.9 Hz), 8.19 (1H, dd, 8.6 Hz,5.3 Hz), 7.30 (1H, d, 2.3 Hz), 7.18 (1H, dd, 9.2 Hz, 2.3 Hz), 7.09 (1H,dd, 8.9 Hz, 2.3 Hz), 7.06-6.96 (1H, m), 4.32-4.22 (1H, m), 4.21-4.12(1H, m), 4.11-4.02 (1H, m), 3.84-3.75 (1H, m), 3.74-3.61 (2H, m), 1.77(6H, s)

LCMS: m/z 400 [M+H]⁺

HPLC retention time: 4.02 min (analysis condition H)

Example 717 Compound W27-((S)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the toluene suspension of sodium t-butoxide (700 mg, 2.5 eq.),8-methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound W1, 500 mg, 2.9mmol) was added dropwise at 0° C. After 15 minutes, the solution turnedinto blackish green color. The mixture solution was added dropwise withmethyl iodide (1.03 g, 2.5 eq.) and stirred at 15° C. overnight. Brownsolid precipitated. The reaction solution was added to saturated aqueoussolution of ammonium chloride/diethyl ether under stirring and cooling.After that, the solution was extracted with diethyl ether, and driedover sodium sulfate. After removing the solvent under reduced pressure,the resulting residues were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain8-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (350 mg).

Thus-obtained 8-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(250 mg, 1.23 mmol) and 3-cyanophenylhydrazine (0.2 g, 1.2 eq.) weredissolved in trifluoroacetic acid (1 mL), and stirred at 120° C. for 1hr under irradiation with microwave. After cooling, the reactionsolution was added with ethyl acetate, washed with water, saturatedaqueous solution of sodium hydrogen carbonate, and saturated brine,dried over magnesium sulfate, and filtered. The residues obtained afterconcentration under reduced pressure were dissolved in THF (3 mL)comprising 10% water and added at room temperature with DDQ (227 mg, 3eq.). The mixture was then stirred at room temperature for 2 hr. Thereaction solution was added with mixture solution of THF/diethyl ether(1:1), washed with 0.5 N aqueous solution of sodium hydroxide andsaturated brine, dried over sodium sulfate, and then filtered. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain7-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(brown solid, 54 mg).

LCMS: m/z 317 [M+H]⁺

HPLC retention time: 1.00 min (analysis condition I)

Example 718 Compound W37-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as Compound A6, the title compound wasprepared from Compound W2.

LCMS: m/z 316 [M+H]⁺

HPLC retention time: 0.93 min (analysis condition I)

Example 719 Compound W4-1 7-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere,7-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(Compound W3, 15 mg, 0.05 mmol) and triphenylphosphine (40 mg, 3 eq.)were added with THF (1 ml), further added dropwise with((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (20 mg, 3 eq.) and 2.19 Ntoluene solution of diethyl azodicarboxylate (68 μL, 3 eq.), and themixture was stirred at 50° C. for 2 hr. After cooling, the reactionsolution was added with ethyl acetate, washed with brine, dried oversodium sulfate, and filtered. The residues obtained after concentrationunder reduced pressure were purified by preparative TLC (ethylacetate/dichloromethane), and the resulting solid was washed withdichloromethane to obtain the target compound (brown powder, 5 mg).

LCMS: m/z 417 [M+H]⁺

HPLC retention time: 1.04 min (analysis condition I)

Example 720 Compound W4-27-((S)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as Compound S7-2, the title compound wasprepared from Compound W4-1.

LCMS: m/z 377 [M+H]⁺

HPLC retention time: 0.88 min (analysis condition I)

Example 721 Compound X11,1-Spiro-4-piperidine-N-paratoluenesulfonyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one

7-Methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 100 mg, 0.568mmol) was dissolved in toluene (4 mL), added with NaH (60% in oil, 68mg, 3 eq.), and stirred at room temperature for 10 min. The mixturesolution was added with bis-(2-iodo-ethyl)-p-toluenesulfonamide (172 mg,0.568 mmol), and stirred at 70° C. for 2 hr under nitrogen stream. Aftercooling, the reaction solution was added to saturated aqueous solutionof ammonium chloride, extracted with ethyl acetate, washed withsaturated brine, and then dried over magnesium sulfate. The residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (hexane:ethyl acetate/3:1) to obtainthe title compound (colorless oily substance, 62 mg, 33%).

LCMS: m/z 400 [M+H]⁺

HPLC retention time: 2.02 min (analysis condition B)

Example 722 Compound X21,1-Spiro-4-piperidine-N-paratoluenesulfonyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one

1,1-Spiro-4-piperidine-N-paratoluenesulfonyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one(Compound X1, 400 mg, 1.0 mmol) and phenylhydrazine (217 mg, 1.5 eq.)were dissolved in acetic acid (6 mL), and the mixture was stirred at120° C. for 4 hr under nitrogen atmosphere. After cooling, the reactionsolution was added to water, extracted with ethyl acetate, washed withsaturated brine, and then dried over magnesium sulfate. The residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (hexane:ethyl acetate/4:1) to obtainthe title compound (brown solid, 185 mg, 43%).

LCMS: m/z 473 [M+H]⁺

HPLC retention time: 7.23 min (analysis condition B)

Example 723 Compound X36,6-Spiro-4-piperidine-N-paratoluenesulfonyl-8-methoxy-5,6-dihydro-benzo[b]carbazol-11-one

6,6-Spiro-4-piperidine-N-paratoluenesulfonyl-8-methoxy-5,6-dihydro-5H-benzo[b]carbazole(Compound X2, 400 mg, 0.848 mmol) and DDQ (770 mg, 4 eq.) were dissolvedin THF (10 mL) and water (2 mL), and then the mixture was stirred at 50°C. for 5 hr. After cooling, the reaction solution was added to saturatedaqueous solution of sodium hydrogen carbonate, extracted with ethylacetate, washed with saturated brine, and then dried over magnesiumsulfate. The residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (hexane:ethylacetate/3:1) to give a solid, which was then washed with ethyl ether toobtain the title compound (yellow solid, 86 mg, 21%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 11.9 (1H, s), 8.22 (2H, m), 7.75 (2H, d),7.60 (4H, m) 7.30 (2H, m), 7.11 (1H, d), 3.81 (2H, m), 3.68 (3H, s),3.62 (2H, m), 2.49 (3H, s), 2.21 (2H, m), 2.10 (2H, m),

LCMS: m/z 487 [M+H]⁺

HPLC retention time: 6.05 min (analysis condition B)

Example 724 Compound X46,6-Spiro-4-piperidine-8-hydroxy-5,6-dihydro-benzo[b]carbazol-11-one

Mixture of6,6-spiro-4-piperidine-N-paratoluenesulfonyl-8-methoxy-5,6-dihydro-benzo[b]carbazol-11-one(Compound X3, 35 mg, 0.072 mmol) and pyridine hydrochloride salt (800mg) was stirred in a sealing tube at 160° C. for 10 hr. After cooling,the reaction solution was added to water, extracted with ethyl acetate,washed with saturated brine, and then dried over magnesium sulfate. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography(dichloromethane:methanol/4:1) to obtain the title compound (yellowsolid, 30 mg, 98%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.20 (1H, m), 8.10 (1H, m), 7.53 (1H, m),7.25 (3H, m), 6.80 (1H, m), 3.60 (2H, m), 3.45 (2H, m), 2.52 (2H, m),2.05 (2H, m).

LCMS: m/z 319 [M+H]⁺

HPLC retention time: 2.86 min (analysis condition B)

Example 725 Compound X58-(2-Diethylaminoethoxy)-6,6-spiro-4-piperidine-8-hydroxy-5,6-dihydro-benzo[b]carbazol-11-one

6,6-Spiro-4-piperidine-8-hydroxy-5,6-dihydro-benzo[b]carbazol-11-one(Compound X4, 30 mg, 0.094 mmol), diethylaminoethanol (22 mg, 2 eq.),triphenylphosphine (50 mg, 2 eq.) and DIAD (39 mg, 2 eq.) were dissolvedin THF (4 mL) and the mixture was stirred at room temperature for 4 hr.The reaction solution was added to water, extracted with ethyl acetate,washed with saturated brine, and then dried over magnesium sulfate. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography(dichloromethane:methanol/4:1) to obtain the title compound (yellow oilysubstance, 6.8 mg, 17%).

LCMS: m/z 418 [M+H]⁺

HPLC retention time: 2.75 min (analysis condition B)

Example 726 Compound Y22,3-Dichloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole

Under nitrogen atmosphere, the acetic acid (1 mL) suspension of7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,92.3 mg, 0.452 mmol) and (3,4-dichlorophenyl)hydrazine hydrochloric acidsalt (Compound Y1, 96.5 mg, 0.452 mmol) was stirred at ambienttemperature of 90° C. for 3.5 hr. After cooling to room temperature, thereaction mixture was added with diethyl ether and water, and theresulting mixture was extracted twice with diethyl ether. The organiclayer was washed three times with water, dried over sodium sulfate, andconcentrated under reduced pressure. The resulting crude product waspurified by flash column chromatography {Merck Kieselgel60, solution forelution: hexane/ethyl acetate (4:1)} to obtain the title compound (paleyellow solid, 62.1 mg, 40%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.92-7.84 (1H, b), 7.62 (1H, s), 7.46 (1H,s), 7.05 (1H, d, 2.6), 6.84 (1H, dd, 8.6 Hz, 2.6 Hz), 4.01 (2H, s), 3.86(3H, s), 1.67 (6H, s)

Example 727 Compound Y32,3-Dichloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the 1,4-dioxane (1.7 mL)-water (0.1 mL)solution of2,3-dichloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole(Compound Y2, 61.0 mg, 0.176 mmol), DDQ (120 mg, 0.529 mmol) was addedand the mixture was stirred at room temperature for 16 hr and 15 min.The reaction mixture was purified by flash column chromatography {MerckKieselgel60, solution for elution: hexane/ethyl acetate (2:1)} to obtainthe title compound (pale orange solid, 16.7 mg, 26%).

¹H-NMR (270 MHz, CDCl₃) δ: 8.55 (1H, s), 8.42-8.36 (1H, b), 8.39 (1H, d,8.6 Hz), 7.54 (1H, s), 7.08 (1H, d, 2.3 Hz), 7.03 (1H, dd, 8.6 Hz, 2.3Hz), 3.93 (3H, s), 1.76 (6H, s)

Example 728 Compound Y42,3-Dichloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Mixture of2,3-dichloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound Y3, 16.5 mg, 0.0457 mmol) and pyridinium chloride (0.2 g) wasstirred at ambient temperature of 160° C. for 7 hr. The reaction mixturewas cooled to room temperature and added with ethyl acetate and water.The mixture was extracted three times with ethyl acetate. The organiclayer was washed twice with water, dried over sodium sulfate, andconcentrated under reduced pressure. The resulting crude product wasused for the next step without further purification (brown solid, 14.8mg, 94%).

¹H-NMR (270 MHz, CD₃OD) δ: 8.34 (1H, s), 8.14 (1H, d, 8.6 Hz), 7.61 (1H,s), 7.10 (1H, d, 2.3 Hz), 6.89 (1H, dd, 8.6 Hz, 2.3 Hz), 1.75 (1H, s)

Example 729 Compound Y5-18-[(1R,5R)-5-(Tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-2,3-dichloro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the THF (0.3 mL) solution of2,3-dichloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound Y4, 12.9 mg, 0.0373 mmol),(4S,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ol(15.5 mg, 0.0559 mmol) and triphenylphosphine (14.7 mg, 0.0559 mmol),toluene solution (25.4 μL, 0.0559 mmol) of DEAD was added dropwise atroom temperature. The reaction mixture was stirred at ambienttemperature of 40° C. for 4 hr. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure, and theresulting crude product was purified by preparative TLC (Merck 60 F254,0.5 mm) {solution for elution: hexane/ethyl acetate (3:1)} to obtain thetitle compound (white solid, 15.1 mg, 67%).

¹H-NMR (270 MHz, CDCl₃) δ: 8.55 (1H, s), 8.44-8.37 (1H, b), 8.37 (1H, d,8.6 Hz), 7.54 (1H, s), 7.15 (1H, d, 2.6 Hz), 7.03 (1H, dd, 8.6 Hz, 2.6Hz), 4.41-4.26 (2H, m), 4.25-4.15 (1H, m), 4.06-3.86 (2H, m), 3.83-3.73(1H, m), 1.76 (3H, s), 1.75 (3H, s), 1.48 (3H, s), 1.47 (3H, s), 0.90(9H, s), 0.092 (6H, s)

Example 730 Compound Y5-22,3-Dichloro-6,6-dimethyl-8-((3R,4R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[b]carbazol-11-one

Under nitrogen atmosphere, to the THF (0.2 mL)-MeOH (0.1 mL) solution of8-[(1R,5R)-5-(tert-butyldimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-2,3-dichloro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one(Compound Y5-1, 14.6 mg, 0.0242 mmol), 0.5 M aqueous solution ofsulfuric acid (96.6 μL, 0.0483 mmol) was added at room temperature. Thereaction mixture was stirred at ambient temperature of 55° C. for 3 hr,cooled to room temperature, and then added with diethyl ether and sodiumhydrogen carbonate (10 mg) in order. The mixture was extracted twicewith diethyl ether, and the organic layer was washed with water andbrine, dried over sodium sulfate, and concentrated under reducedpressure. The resulting crude product was washed with dichloromethane,and dried under reduced pressure to obtain the title compound (whitesolid, 8.3 mg, 76%).

¹H-NMR (270 MHz, CD₃OD) δ: 8.35 (1H, s), 8.24 (1H, d, 8.9 Hz), 7.62 (1H,s), 7.31 (1H, d, 2.3 Hz), 7.10 (1H, dd, 8.9 Hz, 2.3 Hz), 4.31-4.23 (1H,m), 4.12-4.12 (1H, m), 4.11-4.02 (1H, m), 3.84-3.74 (1H, m), 3.73-3.61(1H, m), 1.78 (6H, s)

LCMS: m/z 450 [M+H]⁺

HPLC retention time: 4.92 min (analysis condition H)

Example 731 Compound Z32-[1-(2-Bromo-5-methoxy-phenyl)-1-methylethyl]-benzo[b]thiophene

2-(2-Bromo-5-methoxyphenyl)-2-methyl-propionic acid (1.5 g, 5.5 mmol)was dissolved in methylene chloride (15 mL), added with oxalyl chloride(1.5 mL) and dimethylformamide (2 micro liter) at room temperature, andthe mixture was stirred at room temperature for 30 min. After removingthe solvent, the residues were dissolved in toluene, added at roomtemperature with 2-[(triphenyl-5-phosphanyl)-methyl]-benzenethiolhydrobromide (2.56 g, 5.5 mmol) and triethylamine (2.27 mL), and thenthe mixture was refluxed under heating for 30 min. Thereafter, themixture was cooled to 0° C., added with lithium hexamethyldisilazide (1M tetrahydrofuran solution, 5.5 mL), and refluxed under heating for 24hr. The reaction mixture was extracted with ethyl acetate and washedwith water. The organic layer was dried over magnesium sulfate. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (0.55 g, 28%).

¹H-NMR (270 MHz, CDCl₃) δ: 6.61 (1H, s), 3.37 (3H, s), 1.83 (6H, s)

Example 732 Compound Z42-(1-Benzo[b]thiophen-2-yl-1-methyl-ethyl)-4-methoxy-benzoic Acid

2-[1-(2-Bromo-5-methoxy-phenyl)-1-methylethyl]-benzo[b]thiophene(Compound Z3, 40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (0.5mL), cooled to −78° C., added with n-butyl lithium (1.57 M, hexanesolution, 0.07 mL), and the mixture was stirred for 10 min. The reactionmixture was added with dry ice and then maintained for 1 hr. After that,the mixture was added with 0.5 N hydrochloric acid, extracted with ethylacetate and washed with water. The organic layer was dried overmagnesium sulfate. The residues obtained after concentration underreduced pressure were purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (22 mg, 55%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.46 (1H, d), 7.44 (1H, d), 6.92 (s, 1H),6.70 (d, 1H), 3.84 (s, 3H), 1.89 (6H, s)

Example 733 Compound Z58-Methoxy-6,6-dimethyl-6H-benzo[b]naphth[2,3-d]thiophen-11-one

To 2-(1-benzo[b]thiophen-2-yl-1-methylethyl)-4-methoxy-benzoic acid(Compound Z4, 68 mg, 0.22 mmol), polyphosphoric acid (3.5 g) was added,and the mixture was stirred for 1 hr at 100° C. under heating. Themixture was added with water, extracted with ethyl acetate and washedwith water. The organic layer was dried over magnesium sulfate. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (41 mg, 63%).

LCMS: m/z 309 [M+H]⁺

HPLC retention time: 2.89 min (analysis condition C)

Example 734 Compound Z68-Hydroxy-6,6-dimethyl-6H-benzo[b]naphth[2,3-d]thiophen-11-one

Under the same conditions as Compound A6, the title compound wasprepared from Compound Z5.

LCMS: m/z 295 [M+H]⁺

HPLC retention time: 2.91 min (analysis condition F)

Example 735 Compound Z78-(2-Diethylamino-ethoxy)-6,6-dimethyl-6H-benzo[b]naphth[2,3-d]thiophen-11-one

According to the same method as the method for synthesizing CompoundA7-17, the title compound was prepared from Compound Z6.

LCMS: m/z 394 [M+H]⁺

HPLC retention time: 5.06 min (analysis condition F)

Example 736 Compound Z9 2-Bromo-1,3-dihydroxytetrahydropyranbenzene

To 4-bromo-benzene-1,3-diol (Compound Z8, 20 g, 105.8 mmol) and3,4-dihydro-2H-pyran (38.6 mL), pyridium paratoluenesulfonate (266 mg)was added, and the mixture was stirred at 50° C. for 1 hr. The residuesobtained after concentration under reduced pressure were purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (31.82 mg, 84%).

LCMS: m/z 358 [M+H]⁺

HPLC retention time: 3.15 min (analysis condition C)

Example 737 Compound Z103-(2,4-Dihydroxy-phenyl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,10 g), 2-bromo-1,3-dihydroxytetrahydropyranbenzene (Compound Z9, 20.98g), sodium t-butoxide (5.88 g), palladium acetate (550 mg) andtri-t-butylphosphonium tetrafluoroborate (710 mg), toluene (40 mL) wasadded and the mixture was stirred and heated at 70° C. under nitrogenatmosphere for 6 hr. After cooling, the reaction mixture was added withmethanol (38 mL) and trifluoroacetic acid (14.54 mL) at roomtemperature, and then stirred at room temperature overnight. To theresulting residues, methylene chloride and saturated dipotassiumhydrogen phosphate were added and the organic layer was washed withsaturated brine. Thereafter, the organic layer was dried over magnesiumsulfate. The residues obtained after concentration under reducedpressure were purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (5.53 g, 36%).

LCMS: m/z 312 [M+H]⁺

HPLC retention time: 2.39 min (analysis condition F)

Example 738 Compound Z11 Trifluoromethanesulfonic Acid8-methoxy-6,6-dimethyl-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-ylEster

3-(2,4-Dihydroxy-phenyl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(Compound Z10, 5.53 g) was dissolved in methylene chloride (40 mL), andadded with trifluoromethanesulfonic anhydride (2.98 mL) at roomtemperature. After cooling to 5° C., diisopropylethylamine (9.25 mL) andtrifluoromethanesulfonic anhydride (4.47 mL) were added thereto. To thereaction mixture, methylene chloride and saturated dipotassium hydrogenphosphate were added and the organic layer was washed with saturatedbrine. Thereafter, the organic layer was dried over magnesium sulfate.The residues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (4.82 g, 64%).

LCMS: m/z 427 [M+H]⁺

HPLC retention time: 8.95 min (analysis condition H)

Example 739 Compound Z12 Trifluoromethanesulfonic Acid8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-ylEster

Trifluoromethanesulfonic Acid8-methoxy-6,6-dimethyl-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-ylester (Compound Z11, 4.82 g) was dissolved in acetonitrile (48 mL) andwater (24 mL), added with sodium chlorite (2.55 g) and N—hydroxyphthalimide (369 mg), and then the mixture was stirred at 40° C.for 1 hr. The reaction mixture was added with methylene chloride and theorganic layer was washed with saturated brine. Thereafter, the organiclayer was dried over magnesium sulfate. The residues obtained afterconcentration under reduced pressure were purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (2.80g, 56%).

LCMS: m/z 441 [M+H]⁺

HPLC retention time: 8.02 min (analysis condition H)

Example 740 Compound Z13 Trifluoromethanesulfonic Acid8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-ylEster

Under the same conditions as Compound A6, the title compound wasprepared as a crude product from Compound Z12.

Example 741 Compound Z14 Trifluoro-methanesulfonic Acid8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl Ester

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was obtained as a crude product from Compound Z13 and[5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol(Compound T22-0).

Example 742 Compound Z158-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furane-3-carbonitrile

Trifluoro-methanesulfonic Acid8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl ester(Compound Z14, 24 mg) was dissolved in DMF (0.5 mL), added with zinc(II) cyanide (8.2 mg) and palladium tetrakistriphenylphosphine (2.0 mg),and the mixture was stirred under heating at 200° C. for 20 min withmicrowave irradiation. To the reaction mixture, ethyl acetate was addedand the organic layer was washed with saturated brine. Thereafter, theorganic layer was dried over magnesium sulfate. The residues obtainedafter concentration under reduced pressure were purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain the titlecompound (15 mg).

LCMS: m/z 562 [M+H]⁺

HPLC retention time: 4.14 min (analysis condition F)

Example 743 Compound Z166,6-Dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-benzo[b]naphth[2,3-d]furane-3-carbonitrile

Under the same conditions as Compound S7-2, the title compound wasprepared from Compound Z15.

LCMS: m/z 408 [M+H]⁺

HPLC retention time: 4.51 min (analysis condition H)

Example 744 Compound K7-54-(3-Cyano-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-Butyl Ester

Under the same conditions as the method for synthesizing CompoundB2-22-1, the title compound was prepared from Compound K6 and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester.

LCMS: m/z 498 [M+H]⁺

HPLC retention time: 4.24 min (analysis condition W)

Example 745 Compound K7-69-Methoxy-6,6-dimethyl-11-oxo-8-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1,the title compound was prepared from K7-5.

LCMS: m/z 398 [M+H]⁺

HPLC retention time: 2.57 min (analysis condition W)

Example 746 Compound K8-18-(1-Cyclobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound K7-6 and cyclobutanone.

LCMS: m/z 452 [M+H]⁺

HPLC retention time: 2.72 min (analysis condition W)

Example 747 Compound K8-28-(1-Cyclobutyl-piperidin-4-yl)-9-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing CompoundB3-13-1, the title compound was prepared from Compound K8-1.

LCMS: m/z 454 [M+H]⁺

HPLC retention time: 2.76 min (analysis condition W)

Example 748 Compound K9-58-(1-Cyclobutyl-piperidin-4-yl)-9-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound K8-2.

LCMS: m/z 440 [M+H]⁺

HPLC retention time: 2.57 min (analysis condition W)

Example 749 Compound K10-88-(1-Cyclobutyl-piperidin-4-yl)-9-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound K9-5 and isopropyl iodide.

LCMS: m/z 482 [M+H]⁺

HPLC retention time: 1.74 min (analysis condition S)

The compounds described in the following Tables 2-3 were synthesizedfrom the intermediates of Compound K or Compound L by alkylation ofhydroxyl group according to Mitsunobu reaction used for preparingCompound A7-1 or the method used for the synthesis of Compound A7-17(described in the Table).

TABLE 2 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 750 K10-9

6,6-Dimethyl- 8-(4-morpholin- 4-yl-piperidin-1-yl)- 11-oxo-9-(tetrahydro- pyran-4-yloxy)- 6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile U 1.35 555 A7-1 751 K10-10

9-(2-Methoxy- ethoxy)-5-(2- methoxy-ethyl)- 6,6-dimethyl-8-(4-morpholin-4-yl- piperidin-1-yl)-11- oxo-6,11-dihydro- 5H-benzo[b]carbazole- 3-carbonitrile S 1.50 587 A7-17 752 K10-11

9-(2-Methoxy- ethoxy)-6,6- dimethyl-8-(4- morpholin-4-yl-piperidin-1-yl)-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole-3-carbonitrile S 1.37 529 A7-17 753 K10-12

9-Ethoxy-6,6- dimethyl-8-(4- morpholin-4-yl- piperidin-1-yl)-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile U 1.95 499 A7-17754 K10-13

6,6-Dimethyl-8-(4- morpholin-4-yl- piperidin-1-yl)-11-oxo-9-(tetrahydro- furan-3-yloxy)- 6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile S 1.40 541 A7-1 755 K10-14

9-(2-Diethylamino- ethoxy)-6,6- dimethyl-8-(4- morpholin-4-yl-piperidin-1-yl)-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole-3-carbonitrile S 1.13 570 A7-17 756 K10-15

8-(4-Cyclobutyl- piperazin-1-yl)-9- (2-methoxy- ethoxy)-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S1.45 499 A7-17 757 K10-16

8-(4-Cyclobutyl- piperazin-1-yl)- 5,6,6-trimethyl-11- oxo-9-(tetrahydro-furan-3-yloxy)- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S1.98 525 A7-1 758 K10-17

8-(4-Cyclobutyl- piperazin-1-yl)-9- (1-ethyl-propoxy)-5,6,6-trimethyl-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole-3-carbonitrile S 2.43 525 A7-1 759 K10-18

8-(4-Cyclobutyl- piperazin-1-yl)- 6,6-dimethyl-11- oxo-9-(tetrahydro-furan- 3-yloxy)-6,11- dihydro-5 H- benzo[b]carbazole-3-carbonitrile S 1.92 511 A7-1 760 K10-19

8-(4-Cyclobutyl- piperazin-1-yl)-6,6- dimethyl-11-oxo-9-(tetrahydro-pyran- 4-yloxy)-6,11- dihydro-5H- benzo[b]carbazole-3-carbonitrile U 1.97 525 A7-1 761 K10-20

8-(4-Cyclobutyl- piperazin-1-yl)-9- (1-ethyl-propoxy)- 6,6-dimethyl-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile S 1.32 511 A7-1762 L10-3

9-Isopropoxy-8-(2- methoxy-ethoxy)- 5-(2-methoxy- ethyl)-6,6-dimethyl-11-oxo- 6,11-dihydro-5H benzo[b]carbazole- 3-carbonitrile S2.68 477 A7-17 763 L10-4

9-Isopropoxy-8-(2- methoxy-ethoxy)- 6,6-dimethyl-11- oxo-6,11-dihydro-5H- benzo[d]carbazole- 3-carbonitrile S 2.68 419 A7-17

TABLE 3 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 764 L10-5

8-(1-Cyclobutyl- piperidin-4- ylmethoxy)-9- isopropoxy-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[d]carbazole- 3-carbonitrile S1.65 512 A7-1 765 L10-6

9-Isopropoxy-8-(1- isopropyl-piperidin- 4-ylmethoxy)-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S1.62 500 A7-1 766 L10-7

8-(1-Cyclobutyl- piperidin-3-yloxy)- 9-isopropoxy-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.65 498 A7-1 767L10-8

9-Isopropoxy-8-(1- isopropyl-piperidin- 3-yloxy)-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.59 486 A7-1 768L10-9

8-(2-Diethylamino- ethoxy)-9- isopropoxy-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.07 460 A7-17 769L10-10

9-Isopropoxy-6,6- dimethyl-11-oxo-8- (pyridin-4-yloxy)- 6,11-dihydro-5H-benzo[b]carbazole- 3-carbonitrile U 2.07 438 A7-17 770 L10-11

9-Isopropoxy-6,6- dimethyl-11-oxo-8- vinyloxy-6,11- dihydro-5H-benzo[b]carbazole- 3-carbonitril U 2.77 387 A7-17 771 L10-12

9-Isopropoxy-6,6- dimethyl-11-oxo-8- (tetrahydro-furan- 3-yloxy)-6,11-dihydro-5H- benzo[d]carbazole- 3-carbonitrile S 2.45 431 A7-1

The compounds described in the following Table 4 were synthesized fromthe intermediates of Compound B according to the method described in theTable.

TABLE 4 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 772 B3-39

8-((3R,5S)-4- Cyclobutyl-3,5- dimethyl-piperazin-1- yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 1.90 453 B3-32773 B3-40

8-((3R,5S)-4-Ethyl- 3,5-dimethyl-piperazin- 1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 1.82 427 B3-32774 B2-30

6,6-Dimethyl-8-[4-(1- methyl-piperidin-4-yl)- piperazin-1-yl]-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 1.58 468 B2-1 775B3-41

8-(4- Cyclobutanecarbonyl- piperazin-1-yl)-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 2.35 453 A9-10 776 B3-42

8-(4- Cyclopropanecarbonyl- piperazin-1-yl)-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 2.22 439 A9-10

Example 777 Compound E6-49-Ethyl-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2,the title compound was prepared from Compound E5-1.

LCMS: m/z 331 [M+H]⁺

HPLC retention time: 3.42 min (analysis condition W)

Example 778 Compound E7 Trifuloro-methanesulfonic acid3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylEster

Under the same conditions as the method for synthesizing Compound B1,the title compound was prepared from Compound E6-4.

LCMS: m/z 463 [M+H]⁺

HPLC retention time: 4.39 min (analysis condition W)

Example 779 Compound E8-19-Ethyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was prepared from Compound E7 and piperazine in thesame manner as the method for synthesizing Compound B2-1.

LCMS: m/z 399 [M+H]⁺

HPLC retention time: 1.88 min (analysis condition U)

Example 780 Compound E8-29-Ethyl-6,6-dimethyl-8-((S)-3-methyl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound E7 and2-(S)-methylpiperazine.

LCMS: m/z 413 [M+H]⁺

HPLC retention time: 2.76 min (analysis condition W)

Example 781 Compound E8-38-((3R,5S)-3,5-Dimethyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1,the title compound was prepared from Compound E7 andcis-2,6-dimethylpiperazine.

LCMS: m/z 427 [M+H]⁺

HPLC retention time: 2.00 min (analysis condition U)

Example 782 Compound E8-48-(1-Cyclobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Compound 7 was converted in the same manner as Compound B2-22-1 andCompound 2, and subsequently subjected to reductive amination in thesame manner as Compound B3-32 to obtain the title compound.

LCMS: m/z 450 [M+H]⁺

HPLC retention time: 2.12 min (analysis condition U)

Example 783 Compound E9-18-((S)-4-Cyclobutyl-3-methyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32,the title compound was prepared from Compound E8-2 and cyclobutanone.

LCMS: m/z 467 [M+H]⁺

HPLC retention time: 2.90 min (analysis condition W)

The compounds described in the following Table 5 were prepared byacylation from Compound E8-1 in the same manner as the method forsynthesizing Compound A9-10.

TABLE 5 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 784 E9-2

8-(4- Cyclopropanecarbonyl- piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrileU 2.58 467 785 E9-3

8-(4- Cyclobutanecarbonyl- piperazin-1-yl)-9-ethyl- 6,6-dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 2.74 481 786 E9-4

8-[4-(2- Dimethylamino-acetyl)- piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrileU 1.98 484 787 E9-5

9-Ethyl-8-(4-isobutyryl- piperazin-1-yl)-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 2.67 469 788 E9-6

8-(4-Acetyl-piperazin- 1-yl)-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 2.35 441 789 E9-7

8-(4- Cyclopentanecarbonyl- piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrileS 2.87 495 790 E9-8

8-(4- Cyclohexanecarbonyl- piperazin-1-yl)-9-ethyl- 6,6-dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile S 2.97 509

Example 791 Compound E9-98-[4-(1-Cyano-cyclohexyl)-piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Ethyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(45 mg) and cyclohexanone (25 mg) were suspended in chloroform (2 ml),added with trimethylsilyl cyanide (30 mg) and zinc iodide (5 mg), andthe mixture was stirred at 60° C. for 17 hrs. The reaction mixture wasdiluted with ethyl acetate (20 ml) and the organic layer was washed with10% brine solution and concentrated under reduced pressure. Theresulting residues were purified by silica gel column(dichloromethane/methanol (=99/1)) to obtain the title compound (12 mg,yield 30%).

LCMS: m/z 506 [M+H]⁺

HPLC retention time: 3.00 min (analysis condition U)

The compounds described in the following Table 6 were synthesized fromCompound E8-1 or Compound PR10-1 in the same manner as the method forCompound E9-9.

TABLE 6 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 792 E9-10

8-[4-(1-Cyano- cyclobutyl)-piperazin- 1-yl]-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole-3- carbonitrile U2.88 478 793 PR11-20

8-(4-Cyano-4- hydroxy-piperidine-1- yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole-3- carbonitrile Y3.05 439 794 PR11-21

8-(4-Cyano-4- morpholine-4-yl- piperidine-1-yl)-9-ethyl-6,6-dimethyl-11- oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile Y 3.35 508

With respect to the compounds described in the following Table 7,Compound F2 was subjected to amination in the same manner as CompoundB2-1. Subsequently, the preparation was carried out by reductiveamination in the same manner as the method for Compound B3-32.

TABLE 7 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 795 F3-12

9-Bromo-8-((3R,5S)- 3,5-dimethyl- piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole-3- carbonitrile U2.05 477,479 B2-1 796 F4-11

9-Bromo-8-((3R,5S)- 4-cyclobutyl-3,5- dimethyl-piperazin-1-yl)-6,6-dimethyl-11- oxo-6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile U 2.28 531,533 B3-32

Example 797 Compound PR1 2-(4-Vinylphenyl)-2-methylpropanoic Acid

2-(4-Bromophenyl)-2-methylpropanoic acid (30 g), PPh₃ (5.0 g), potassiumvinyltrifluoroborate (24.8 g), potassium carbonate (51.2 g), andpalladium acetate (1.43 g) were dissolved in 1-propanol (198 ml) anddistilled water (99 ml). After deaeration, the mixture was stirred underreflux for 6 hrs under nitrogen atmosphere. Insoluble matters wereremoved by filtration and washed with 1-propanol (210 ml). The filtratewas then concentrated under reduced pressure. Concentrated residues werepartitioned between CPME (300 ml) and distilled water (150 ml,comprising 4.17 ml of ethylenediamine). The organic layer was removedand the aqueous layer was adjusted to pH 5 by using 2 N hydrochloricacid. The aqueous layer was extracted with a mixture of isopropylacetate (240 ml) and heptane (240 ml). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure.Ethanol (300 ml) was added thereto for suspending and washing theresultant. The solid was removed by Celite filtration, and the filtratewas concentrated under reduced pressure to obtain the title compound(21.7 g, 93%).

¹H-NMR (400 MHz CDCl₃) δ ppm 7.49-7.34 (4H, m), 6.69 (1H, dd, J=17.6,11.0 Hz), 5.72 (1H, d, J=17.6 Hz), 5.23 (1H, d, 11.0 Hz), 1.59 (s, 6H)

HPLC retention time: 2.05 min (analysis condition S)

Example 798 Compound PR2 2-(4-Ethylphenyl)-2-methylpropanoic Acid

2-(4-Vinylphenyl)-2-methylpropanoic acid (58 g) was dissolved inethanol, and then stirred for 3 hrs under atmospheric hydrogen pressurein the presence of 10% palladium carbon (5.8 g). The catalyst wasremoved by filtration, and the filtrate was concentrated to obtain acrude product, which was then suspended and washed with hexane to givethe title compound (56.5 g, 94.8%).

¹H-NMR (270 MHz DMSO-d₆) δ ppm 12.28 (1H, s), 7.27-7.22 (2H, m),7.18-7.14 (2H, m), 2.56 (2H, q, J=7.6 Hz), 1.45 (6H, s), 1.16 (3H, t,J=7.6 Hz)

LCMS: m/z 193 [M+H]⁺

HPLC retention time: 2.18 min (analysis condition S)

Example 799 Compound PR3 2-(4-Ethyl-3-iodophenyl)-2-methylpropanoic Acid

2-(4-Ethylphenyl)-2-methylpropanoic acid (58.1 g, 302.2 mmol) wasdissolved in acetic acid (175 ml), added with N-iodosuccinimide (71.4 g,317.3 mmol, 1.05 eq.) and conc. sulfuric acid (75 ml) at 0° C.Thereafter, the mixture was stirred at room temperature for 2 hrs. Aftercooling the reaction solution to 0° C., 10% aqueous solution of sodiumhydrogen sulfite (100 ml) was added and the mixture was stirred for 1hr. H₂O (450 ml) was added to the mixture and the precipitated solid wasfiltered to obtain the title compound as a crude product. Ethanol (150ml) and 10% aqueous solution of sodium hydrogen sulfite (50 ml) wereadded to the crude product, and the mixture was dissolved under heatingat 50° C. After confirming the dissolution, the solution was cooled toroom temperature, added with H₂O (300 ml), and then stirred at 0° C. for1 hr. The precipitated solid was filtered to obtain the title compound(95.8 g, 99%).

¹H-NMR (270 MHz DMSO-d₆) δ ppm 12.46 (1H, s), 7.70 (1H, d, J=1.8 Hz),7.32 (1H, dd, J=8.1, 1.8 Hz), 7.26 (1H, d, J=8.1 Hz), 2.64 (2H, q, J=7.5Hz), 1.43 (6H, s), 1.12 (3H, t, J=7.5 Hz)

HPLC retention time: 2.53 min (analysis condition S)

Example 800 Compound PR4 Tert-butyl4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic Acid

Mono-tert-butyl malonic acid (72.5 g) was dissolved in DME (360 ml),added with TEA (189 ml) and magnesium chloride (29.63 g) and the mixturewas stirred for 2 hrs. In a separate vessel, CDI (52.75 g) was added tothe DME (360 ml) solution of 2-(4-ethyl-3-iodophenyl)-2-methylpropanoicacid (90 g) and stirred at room temperature for 1 hr to prepare asolution. This solution was then added dropwise to the aforementionedmixture, and the resulting solution was washed with DME (90 ml) andstirred at 70° C. for 3 hrs. The reaction mixture was diluted withisopropyl acetate (225 ml) and heptane (225 ml), and the organic layerwas washed with 2 N hydrochloric acid (684 ml), 0.17 N hydrochloric acid(540 ml), 15% aqueous solution of ammonium chloride (540 ml), 1 Naqueous solution of sodium hydroxide (540 ml) and 15% brine (540 ml) inorder. The organic layer was concentrated under reduced pressure toobtain the title compound as a crude product, which was used for thenext step without further purification.

¹H-NMR (270 MHz DMSO-d₆) δ: 7.64 (1H, d, J=2.0 Hz), 7.30 (1H, d, J=8.1Hz), 7.24 (1H, d, J=8.0, 2.0 Hz), 3.32 (2H, s), 2.65 (2H, q, J=7.4 Hz),1.40 (6H, s), 1.34 (9H, s), 1.13 (3H, t, J=7.4 Hz)

Example 801 Compound PR5-1 Tert-butyl6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylicAcid

4-(4-Ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl (117.76g) was dissolved in DMF (471 ml) and added with cesium carbonate (276.5g). DMF solution (176.6 ml) of 4-chloro-3-nitrobenzonitrile (63.9 g) wasadded dropwise thereto (washed with DMF 58.8 ml), and the mixture wasstirred at 35° C. for 6 hrs. To the mixture, THF (588.8 ml), ethylacetate (588.8 ml), acetic acid (72.87 ml) and distilled water (588.8ml) were added for distribution, and the aqueous layer was removed. Theorganic layer was added with THF (588.8 ml) and water (588.8 ml), andunder stirring sodium hydrosulfite (80%, 147.76 g) was added in smallportions and the mixture was stirred at room temperature for 3 hrs.After removing the aqueous layer, the organic layer was washed with 15%brine (588.8 ml). The organic layer was added with 1 N hydrochloric acid(94.2 ml), stirred for 1 hr, and then added with 1 N aqueous solution ofsodium hydroxide (329.7 ml). The aqueous layer was removed and theorganic layer was concentrated under reduced pressure. The concentratedresidues were dissolved in ethanol (824.3 ml) and added dropwise withdistilled water (247.3 ml). The resulting precipitated crystals werefiltered and collected, washed with water:ethanol (=1:2 mixturesolution, 588.8 ml), and then dried to obtain the title compound (98.12g, two-step 63.5%).

¹H-NMR (270 MHz DMSO-d₆) δ: 12.04 (1H, br. s), 8.01 (1H, d, J=8.4 Hz),7.91 (1H, d, J=0.8 Hz), 7.55 (1H, d, J=1.8 Hz), 7.49 (1H, dd, J=1.5, 8.4Hz), 7.16 (1H, d, J=8.1 Hz), 7.07 (1H, dd, J=2.0, 8.1 Hz), 2.58 (2H, q,J=7.4 Hz), 1.79 (6H, s), 1.23 (9H, s), 1.06 (3H, t, J=7.4 Hz)

LCMS: m/z 459, 515 [M+H]⁺

Example 802 Compound PR5-2 Methyl6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylicAcid

The title compound was prepared from monomethyl malonate and2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid in the same manner asthe method for Compound PR4 and Compound PR5-1.

¹H-NMR (270 MHz DMSO-D₆) δ: 12.20 (s, 1H), 8.06-8.03 (m, 1H), 7.95-7.94(m, 1H), 7.58-7.57 (m, 1H), 7.53-7.49 (m, 1H), 7.17-7.14 (m, 1H),7.06-7.02 (m, 1H), 3.46 (s, 3H), 2.65-2.56 (q, 2H, J=7.5 Hz), 1.78 (s,6H), 1.12-1.07 (t, 3H, J=7.5 Hz)

LCMS: m/z 473 [M+H]⁺

Example 803 Compound PR6 Tert-Butyl6-cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl)propan-2-yl)-1H-indole-3-carboxylicAcid Hydrochloric Acid Salt

Tert-butyl6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylicacid (390.5 g), 4-morpholin-4-yl piperidine (158 g), and1,3-bis-(2,6-diisopropylphenyl)-imidazoyl-2-ylidene (allyl) palladium(II) chloride (8.83 g) were dissolved in a mixture of NaHMDS (1.9 M, THFsolution 1.32 L) and DME (1.95 L) under nitrogen stream, and the mixturewas stirred at 40° C. for 1 hr. The reaction mixture was thenpartitioned between isopropyl acetate (1.95 L) and 20% aqueous solutionof ammonium chloride (1.95 L). The organic layer was washed twice with10% brine (1.56 L), and then concentrated under reduced pressure. Theresulting residues were dissolved in a mixture of DME (3.9 L) and water(78.1 ml), added with N-acetylcysteine (12.39 g), and stirred at 45° C.for 1 hr. After that, the insoluble matters were filtered and washedwith DME (1.95 L). The filtrate was concentrated under reduced pressure.The resulting residues were dissolved in acetone (5.5 L) and added withthe solution in which pyridinium chloride (96.5 g) is dissolved inacetone (195 ml) and ethanol (78 ml). The precipitated solid wasfiltered, collected, washed with acetone (1.95 L) and dried to obtainthe title compound (373 g, 83%).

¹H-NMR (400 MHz DMSO-D₆) δ: 12.03 (1H, s), 10.75-10.88 (1H, m), 7.99 (1H, d, J=8.3 Hz), 7.93 (1H, d, J=1.3 Hz), 7.46 (1H, dd, J=1.3, 8.1 Hz),7.10 (1H, d, J=7.9 Hz), 6.88 (1H, dd, J=1.7, 7.9 Hz), 6.79 (1H, d, J=1.7Hz), 3.91-4.01 (2H, m), 3.76-3.87 (2H, m), 3.37-3.46 (2H, m), 3.22 (1H,m), 2.94-3.11 (4H, m), 2.57 (2H, q, J=7.5 Hz), 2.45-2.53 (2H, m),2.09-2.16 (2H, m), 1.80 (6H, s), 1.71-1.77 (2H, m), 1.19 (9H, s), 1.14(3H, t, J=7.5 Hz)

LCMS: m/z 557 [M+H]⁺

Example 804 Compound PR76-Cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl)propan-2-yl)-1H-indole-3-carboxylicAcid

Tert-butyl6-cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl)propan-2-yl)-1H-indole-3-carboxylicacid hydrochloric acid salt (1400 g) was suspended in TFE (7 L) undernitrogen stream, and added dropwise with TMSCl (554 ml) at 8° C. Afterstirring for 3 hrs, the reaction solution was added with acetone (5.6 L)and aqueous solution of NaOH (1 N, 4.39 L), and 10% aqueous solution ofK₂HPO₄ (1.4 L) was added thereto for neutralization. The precipitatedsolid was filtered and collected, washed twice with a mixture solutionof water:acetone (=1:1, 2.8 L), and dried to obtain the title compound(1061 g, 96.6%).

¹H-NMR (270 MHz DMSO-D₆) δ: 11.95 (1H, s), 11.92 (1H, bs), 8.04 (1H, d,J=8.4 Hz), 7.89 (1H, d, J=1.3 Hz), 7.44 (1H, J=dd, 1.3, 8.4 Hz), 7.00(1H, d, J=8.4 Hz), 6.88 (1H, d, J=1.8 Hz), 6.71 (1H, dd, J=2.2, 7.9 Hz),3.50-3.55 (4H, m), 2.92-2.96 (2H, m), 2.54 (2H, q, 7.5 Hz), 2.39-2.50(6H, m), 2.15-2.22 (1H, m), 1.74-1.85 (8H, m), 1.43-1.52 (2H, m), 1.13(3H, t, J=7.5 Hz)

LCMS: m/z 501 [M+H]⁺

HPLC retention time: 1.53 min (analysis condition U)

Example 805 Compound F6-209-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6-Cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl)propan-2-yl)-1H-indole-3-carboxylicacid (500 g) was dissolved in a mixture of DMA (9.4 L), acetic anhydride(270 ml) and DIPEA (1170 ml) under nitrogen stream. The mixture wasstirred at 90° C. for 1 hr. After cooling to room temperature, themixture was added with methanol (3.525 L) and subsequently withdistilled water (5.875 L). The precipitated solid was filtered,collected, washed twice with the mixture solution (methanol:water=3:5,1.41 L), and then dried to obtain the title compound (389.6 g, 85%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.70 (1H, s), 8.32 (1H, d, J=7.9 Hz), 8.04(1H, s), 8.00 (1H, s), 7.61 (1H, d, J=8.5 Hz), 7.34 (1H, s), 3.64-3.57(4H, m), 3.27-3.18 (2H, m), 2.82-2.66 (4H, m), 2.39-2.28 (1H, m),1.96-1.87 (2H, m), 1.76 (6H, s), 1.69-1.53 (2H, m), 1.29 (3H, t, J=7.3Hz)

LCMS: m/z 483 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition U)

Hydrochloric Acid Salt of Compound F6-20

9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(400 g) was dissolved in a mixture solvent of methylethyl ketone (4.8L), acetic acid (1.44 L) and distilled water (1.68 L) at roomtemperature. The resulting solution was added dropwise to the mixture ofethanol (12 L) and 2 N hydrochloric acid (0.8 L). The precipitated solidwas filtered, washed with ethanol (2 L), and dried to obtainhydrochloric acid salt of Compound F6-20 (357 g).

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.83 (1H, s), 10.78 (1H, s), 8.32 (1H, d,J=8.1 Hz), 8.06 (1H, s), 8.01 (1H, s), 7.61 (1H, d, J=8.1 Hz), 7.37 (1H,s), 4.02 (2H, m), 3.85 (2H, m), 3.51 (2H, m), 3.34 (1H, m), 3.32 (2H,m), 3.15 (2H, m), 2.81 (2H, dd, J=11.98, 11.7 Hz), 2.72 (2H, q, J=7.5Hz), 2.23 (2H, m), 1.89 (2H, m), 1.77 (6H, s), 1.29 (3H, t, J=7.5 Hz)

FABMS: m/z 483.4 [M+H]⁺

Example 806 Compound F6-229-Ethyl-6,6-dimethyl-10-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

From the filtrate solution obtained from the synthesis of CompoundF6-20, the title compound was obtained.

¹H-NMR (400 MHz DMSO-D₆) δ: 12.56 (1H, s), 8.32 (1H, d, J=7.9 Hz), 7.96(1H, s), 7.45-7.59 (3H, m), 3.55-3.62 (4H, m), 3.36-3.50 (2H, m),2.75-2.86 (2H, m), 2.71 (2H, q, J=7.5 Hz), 2.45-2.56 (4H, m), 2.27-2.38(1H, m), 1.73-1.84 (2H, m), 1.69 (6H, s), 1.43-1.58 (2H, m), 1.21 (3H,t, J=7.5 Hz).

LCMS: m/z 483 [M+H]⁺

HPLC retention time: 1.52 min (analysis condition U)

Example 807

Compound PR8

9-Ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Tert-butyl6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylicacid (11 g) was dissolved in Eaton's reagent (200 g) and stirred at roomtemperature for 30 min. The reaction solution was diluted withacetonitrile (200 ml) and distilled water (400 ml). The precipitatedsolid was collected by filtration, washed with distilled water, and thendried. The crude product was dissolved in DMA (45 ml), diluted withacetonitrile (20 ml) and distilled water (18 ml), and re-precipitated toobtain the title compound (6.62 g, 70%).

¹H-NMR (400 MHz DMSO-D₆) δ: 12.79 (1H, s), 8.32-8.29 (2H, m), 8.06 (1H,s), 8.01 (1H, s), 7.62 (1H, dd, J=1.3, 7.9 Hz), 2.78 (2H, q, J=7.5 Hz),1.75 (6H, s), 1.20 (3H, t, J=7.5 Hz)

LCMS: m/z 441 [M+H]⁺

HPLC retention time: 3.17 min (analysis condition U)

Example 808 Compound PR9-18-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The dioxane solution (50 ml) of9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(5.0 g), 1,4-dioxa-8-aza-spiro[4.5]decane (2.08 ml), Pd₂(dba)₃ (520 mg),and S-Phos (963 mg) was flushed with nitrogen gas, added with NaHMDS(1M, THF solution 40 ml), and stirred at 60° C. for 1 hr. The resultingmixture was diluted with ethyl acetate (200 ml). The organic layer waswashed three times with 10% brine, and then concentrated under reducedpressure to obtain the title compound as a crude product. This crudeproduct was used for the next step without further purification.

LCMS: m/z 456 [M+H]⁺

HPLC retention time: 2.78 min (analysis condition U)

Example 809 Compound PR9-29-Ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

As a by-product of Compound PR9-1, the target compound was obtainedaccording to silica gel column separation of Example 810.

LCMS: m/z 315 [M+H]⁺

HPLC retention time: 2.77 min (analysis condition U)

Example 810 Compound PR10-19-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile,which had been prepared in Example 809, was dissolved in THF (10 ml),added with 5 N hydrochloric acid (50 ml), and the mixture was stirredfor 17 hrs. The reaction mixture was neutralized with 5 N aqueoussolution of sodium hydroxide and diluted with ethyl acetate (200 ml).The organic layer was washed with 10% brine, and then concentrated underreduced pressure. The resulting residues were purified by silica gelcolumn (dichloromethane/methanol=99/1 to 90/10) to obtain the titlecompound (2.9 g, two step yield 64%).

¹H-NMR (400 MHz DMSO-D₆) δ: 12.70 (1H, s), 8.32 (1H, d, J=8.4), 8.07(1H, s), 7.99 (1H, s), 7.60 (1H, dd, J=1.3, 7.9 Hz), 7.42 (1H, s), 3.28(4H, t, J=5.7), 2.80 (q, 2H, J=7.5 Hz), 2.55 (4H, t, J=5.7), 1.75 (6H,s), 1.31 (3H, t, J=7.5 Hz)

LCMS: m/z 412 [M+H]⁺

HPLC retention time: 2.57 min (analysis condition U)

Example 811 Compound PR11-19-Ethyl-6,6-dimethyl-11-oxo-8-[4-(3-oxo-piperazin-1-yl)-piperidin-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(30 mg) and 2-ketopiperazine (10 mg) were dissolved in THF (2 ml), addedwith sodium triacetoxy borohydride (30 mg), and the mixture was stirredat 30° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate(20 ml). The organic layer was washed with 10% brine, and thenconcentrated under reduced pressure. The resulting residues werepurified by silica gel column (dichloromethane/methanol=99/1 to 90/10)to obtain the title compound (11.5 mg, yield 32%).

LCMS: m/z 496 [M+H]⁺

HPLC retention time: 1.90 min (analysis condition U)

Example 812 Compound PR11-29-Ethyl-8-(4-hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

As a by-product of Compound PR11-1, the target compound was obtained.

LCMS: m/z 414 [M+H]⁺

HPLC retention time: 2.13 min (analysis condition S)

The compounds described in the following Tables 8-10 were synthesized byintroducing a corresponding amine to9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrileaccording to the method used for the synthesis of Compound PR9-1.Although the relevant literatures are not entirely known, some amines inwhich a tertiary alkyl group is attached to the nitrogen atom wereprepared according to the method described in Journal of MedicinalChemistry, 45 (14), 3143-3160, 2002. Alternatively, the preparation wascarried out by introducing a corresponding amine to9-ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrilebased on the method that is used for the synthesis of Compound PR11-1(i.e., reductive amination).

TABLE 8 Example HPLC Retention No. Comp. No. Structure Compound NameCondition Time m/z 813 PR9-3

8-(4-tert-Butyl- piperazin-1-yl)-9- ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.63 455 814 PR9-4

9-Ethyl-6,6- dimethyl-11-oxo-8- (4-pyrrolidin-1-yl- piperidin-1-yl)-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.13 467 815 PR9-5

9-Ethyl-8-(4- isopropyl- piperazin-1-yl)-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.08 441 816 PR9-6

9-Ethyl-6,6- dimethyl-8-(4- methyl-piperazin- 1-yl)-11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 1.97 413 817 PR9-7

9-Ethyl-8-(4-ethyl- piperazin-1-yl)-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.03 427 818 PR9-8

9-Ethyl-6,6- dimethyl-8- morpholin-4-yl-11- oxo-6,11-dihydro- 5H-benzo[b]carbazole- 3-carbonitrile U 2.65 400 819 PR11-3

8-[4-((2R,6S)-2,6- Dimethyl- morpholin-4-yl)- piperidin-1-yl]-9-ethyl-6,6-dimethyl- 11-oxo-6,11- dihydro-5H- benzo[b]carbazole-3-carbonitrile S 1.65 511 820 PR11-4

8- [1,4′]Bipiperidinyl- 1′-yl-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.63 481 821 PR11-5

8-(4,4-Difluoro- [1,4′]bipiperidinyl- 1′-yl)-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonilrile S1.70 517 822 PR11-6

8-(4-Azetidin-1-yl- piperidin-1-yl)-9- ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.55 453 823 PR11-7

9-Ethyl-8-(4- hydroxy- [1,4′]bipiperidinyl- 1′-yl)-6,6-dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 1.95 497824 PR9-9

8-(4-Cyclopropyl- 4-hydroxy- piperidin-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.53 454825 PR11-8

9-Ethyl-8-(4- fluoro- [1,4′]bipiperidinyl- 1′-yl)-6,6-dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.13 499826 PR9-10

9-Ethyl-6,6- dimethyl-8-(3- morpholin-4-yl- azetidin-1-yl)-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile S 1.48 455

TABLE 9 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 827 PR9-11

9-Ethyl-6,6- dimethyl-11-oxo-8- (3-piperidin-1-yl- azetidin-1-yl)-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile S 1.57 453 828 PR9-12

9-Ethyl-6,6- dimethyl-8-[4-(1- methyl-piperidin-4- yl)-piperazin-1-yl]-11-oxo-6,11- dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 1.70 496829 PR9-13

9-Ethyl-6,6- dimethyl-8-[4-(4- methyl-piperazin- 1-yl)-piperidin-1-yl]-11-oxo-6,11- dihydro-5H- benzo[d]carbazole- 3-carbonitrile U 1.73496 830 PR11-9

8-(4-Cyclopentyl- piperazin-1-yl)-9- ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U 2.12 467 831 PR11-10

9-Ethyl-8-[4-(2- hydroxy- ethylamino)- piperidin-1-yl]-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U1.90 457 832 PR11-11

9-Ethyl-8-[4-(3- hydroxy- propylamino)- piperidin-1-yl]-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[d]carbazole- 3-carbonitrile S1.90 471 833 PR9-14

9-Ethyl-6,6- dimethyl-8-(4- methyl-4- morpholine-4-yl-piperidine-1-yl)-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole-3-carbonitrile U 2.00 497 834 PR9-15

9-Ethyl-8-[4-(1- ethyl-cyclobutyl)- piperazine-l-yl]- 6,6-dimethyl-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile Y 2.25 481 835PR9-16

9-Ethyl-8-(4- ethyl-4- morpholine-4-yl- piperidine-1-yl)6,6-dimethyl-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrileY 2.17 511 836 PR9-17

3-Ethyl-8-(4- isopropyl-4- morpholine-4-yl- piperidine-1-yl)-6.6-dimethyl-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrileU 2.12 525 837 PR9-18

9-Ethyl-6,6- dimethyl-11-oxo-8- [4-(1-propyl- cyclobutyl)-piperazine-1-yl]- 6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile U2.23 495 838 PR9-19

9-Ethyli-8-[4-(1- isopropyl- cyclobutyl)- piperazine-1-yl]-6,6-dimethyl-11- oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonrtrileU 2.25 495 839 PR9-20

9-Ethyl-6,6- dimethyl-8-(2- morpholine-4-yl- ethylamino)-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-carbonitrile Y 1.85 443 840PR9-21

9-Ethyl-6,6- dimethyl-11-oxo-8- (2-piperidine-1-yl- ethylamino)-6,11-dihydro-5H- benzo[b]carbazole- 3-carbonitrile Y 1.85 441

TABLE 10 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 841 PR11-12

8-(4-Amino- piperidine-1-yl)-9- ethyl-6,6-dimethyl- 11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile U 1.92 413 842 PR11-13

9-Ethyl-6,6- dimethyl-8-(4- 2,2,3,3,5,5,6,6-d8- morpholine-4-yl-piperidine-1-yl)- 11-oxo-6,11- dihydro-5H-benzo [b]carbazole-3-carbonitrile U 1.98 491 843 PR9-22

9-Ethyl-8-[4-(2- methoxy-ethoxy)- piperidine-1-yl]-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y 3.23 472 844 PR9-23

8-[4-(2-Ethoxy- ethoxy)-piperidine-1- yl]-9-ethyl-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y 3.35 486 845 PR9-24

8-(4- Cyclopropylmethoxy- piperidine-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3- carbonitrile Y 3.50 463846 PR9-25

8-[4-(2-Cyclohexyl- ethoxy)-piperidine-1- yl]-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y4.00 524 847 PR11-14

8-(4- Cyclohexylamino- piperidine-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3- carbonitrile Y 2.33 495848 PR11-15

8-(4- Cyclopentylamino- piperidine-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3- carbonitrile Y 2.15 481849 PR11-16

8-[4- (Cyclopropylmethyl- amino)-piperidine-1- yl]-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y2.15 467 850 PR11-17

8-(4- Cyclopropylamino- piperidine-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3- carbonitrile Y 2.08 453851 PR11-18

8-(4- Cyclobutylamino- piperidine-1-yl)-9- ethyl-6,6-dimethyl-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole-3- carbonitrile Y 2.13 457852 PR11-19

8-[4- (Cyclohexylmethyl- amino)-piperidine-1- yl]-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazole-3- carbonitrile Y2.42 509

Example 853 Compound PR11-229-Ethyl-8-(4-hydroxyimino-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(30 mg) and hydroxylamine hydrochloric acid salt (10 mg) were dissolvedin ethanol (5 ml) and stirred at 60° C. for 6 hrs. The reaction mixturewas diluted with ethyl acetate (20 ml). The organic layer was washedwith 10% brine and concentrated under reduced pressure. The resultingresidues were purified by silica gel column(dichloromethane/methanol=99/1 to 90/10) to obtain the title compound(23.5 mg, yield 74%).

LCMS: m/z 427 [M+H]⁺

HPLC retention time: 3.08 min (analysis condition Y)

Example 854 Compound PR10-29-Ethyl-6,6-dimethyl-5-(2-morpholin-4-yl-ethyl)-8-(2-morpholin-4-yl-ethylamino)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Ethyl-6,6-dimethyl-8-(2-morpholin-4-yl-ethylamino)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(10 mg) was dissolved in DMF (1 ml), added with K₂CO₃ (10 mg) and1-(2-chloroethyl)morpholine (8 mg), and then stirred at 90° C. for 17hrs. The reaction mixture was diluted with ethyl acetate (10 ml). Theorganic layer was washed with 10% brine and concentrated under reducedpressure. The resulting residues were purified by silica gel column(dichloromethane/methanol=99/1 to 90/10) to obtain the title compound(6.4 mg, yield 58%).

LCMS: m/z 556 [M+H]⁺

HPLC retention time: 1.78 min (analysis condition Y)

Example 855 Compound F79-Ethyl-6,6-dimethyl-11-oxo-8-[4-(4-oxy-morpholin-4-yl)-piperidin-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(400 mg) was dissolved in trifluoroethanol (80 ml), added with 30%hydrogen peroxide solution (0.8 ml), and the mixture was stirred at 60°C. for 17 hrs. The reaction mixture was concentrated to 30 ml anddiluted with water (20 ml). The precipitated matter was collected byfiltration and dried to obtain the title compound (375 mg, yield 90%).

LCMS: m/z 499 [M+H]⁺

HPLC retention time: 2.05 min (analysis condition U)

Example 856 Compound FR16-Cyano-2-[1-(4-ethyl-3-iodophenyl)-1-methyl-ethyl]-benzofuran-3-carboxylicAcid Tert-Butyl Ester

4-(4-Ethyl-3-iodo-phenyl)-4-methyl-3-oxo-pentanoic acid tert-butyl ester(1.00 g, 2.40 mmol) was dissolved in NMP (4 ml), added with cesiumcarbonate (1.56 g, 4.80 mmol, 2.0 eq.), and the mixture was stirred for5 min. The NMP solution (2 ml) of 4-chloro-3-nitro-benzonitrile (542 mg,2.88 mmol, 1.2 eq.) was added thereto, and the mixture was stirred at50° C. for 64 hrs under nitrogen atmosphere. After cooling to roomtemperature, ethyl acetate (20 ml) was added and the organic layer waswashed with saturated aqueous solution of ammonium chloride (20 ml). Theorganic layer was further washed with saturated brine and dried oversodium sulfate. The drying agent was removed by filtration and theresidues obtained after concentration under reduced pressure werepurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (white amorphous, 320 mg, 26%).

LCMS: m/z 516 [M+H]⁺

Example 857 Compound FR26-Cyano-2-{1-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}-benzofuran-3-carboxylicAcid Tert-Butyl Ester

6-Cyano-2-[1-(4-ethyl-3-iodophenyl)-1-methyl-ethyl]-benzofuran-3-carboxylicacid tert-butyl ester was converted to obtain the title compound in thesame manner as the method for Compound PR6.

LCMS: m/z 558 [M+H]⁺

Example 858 Compound FR36-Cyano-2-{1-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}-benzofuran-3-carboxylicAcid Hydroiodic Acid Salt

To obtain the title compound,6-Cyano-2-{1-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}-benzofuran-3-carboxylicacid tert-butyl ester was deprotected by using trimethylsilyl iodide inthe same manner as the method for Compound PR7.

LCMS: m/z 502 [M+H]⁺

Example 859 Compound FR49-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-3-carbonitrile

6-Cyano-2-{1-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}-benzofuran-3-carboxylicacid hydroiodic acid salt was converted in the same method as Example805 to obtain the target compound.

LCMS: m/z 484 [M+H]⁺

Example 860 Compound LB12-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-2-methyl-propionicAcid

The title compound was prepared from2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid by carrying outamination in the same manner as the method for synthesizing CompoundPR6.

LCMS: m/z 361 [M+H]⁺

Example 861 Compound LB22-{1-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}-6-iodo-1H-indole-3-carboxylicAcid Tert-Butyl Ester

2-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-2-methyl-propionicacid was converted in the same manner as the method for synthesizingCompound PR5-1 to obtain the title compound.

LCMS: m/z 658 [M+H]⁺

HPLC retention time: 2.76 min (analysis condition U)

Example 862 Compound LB32-{1-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}-6-iodo-1H-indole-3-carboxylicAcid

2-{1-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}-6-iodo-1H-indole-3-carboxylicacid tert-butyl ester was deprotected in the same manner as the methodfor preparing Compound PR7 to obtain the title compound.

LCMS: m/z 602 [M+H]⁺

HPLC retention time: 2.17 min (analysis condition U)

Example 863 Compound LB49-Ethyl-3-iodo-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-5,6-dihydro-benzo[b]carbazol-11-one

2-{1-[4-Ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-1-methyl-ethyl}-6-iodo-1H-indole-3-carboxylicacid was converted in the same manner as Example 805 to obtain the titlecompound.

LCMS: m/z 584 [M+H]⁺

HPLC retention time: 2.25 min (analysis condition U)

The compounds described in the following Table 11 were converted andprepared from9-ethyl-3-iodo-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-5,6-dihydro-benzo[b]carbazol-11-oneaccording to the method described in the Table.

TABLE 11 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 864 LB5-1

N-[9-Ethyl-6,6- dimethyl-8-(4- morpholine-4-yl- piperidine-1-yl)-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-yl]-benzamide Y 1.78 577B2-10 865 LB5-2

9-Ethyl-3- ethylsulfanyl-6,6- dimethyl-8-(4- morpholine-4-yl-piperidine-1-yl)-5,6- dihydro- benzo[b]carbazole- 11-one Y 2.28 518B2-17 866 LB5-3

N-[9-Ethyl-6,6- dimethyl-8-(4- morpholine-4-yl- piperidine-1-yl)-11-oxo-6,11-dihydro- 5H- benzo[b]carbazole- 3-yl]-acetamide Y 1.50 515B2-10

Example 867 Compound AZ1 Methanesulfonic Acid(2-fluoropyridin-4-yl)methyl Ester

(2-Fluoropyridin-4-yl) methanol (1 g) was dissolved in DCM (40 ml),added with TEA (3.3 ml) and mesyl chloride (0.67 ml), and the mixturewas stirred at 0° C. for 1 hr. The mixture was concentrated and thenpurified by silica gel column (n-hexane/ethyl acetate=4/1) to obtain thetitle compound (1.18 g, 77%).

¹H-NMR (270 MHz DMSO-d₆) δ: 3.21 (3H, s), 5.38 (2H, s), 7.22 (1H, s),7.39 (1H, d, J=5.0), 8.29 (1H, d, J=5.0)

Example 868 Compound AZ2 (2-Fluoropyridin-4-yl)acetonitrile

To the DMF (28 ml) solution of methanesulfonic acid(2-fluoropyridin-4-yl)methyl ester (1.16 g), sodium cyanide (0.42 g) wasadded and the mixture was stirred at 80° C. for 1 hr. The mixture wasdiluted with ethyl acetate (100 ml), and washed with 15% brine anddistilled water in order. The organic layer was concentrated andpurified by silica gel column (n-hexane/ethyl acetate=5/1) to obtain thetitle compound (278 mg, 36%).

¹H-NMR (270 MHz DMSO-d₆) δ: 4.22 (2H, s), 7.18 (1H, s), 7.36 (1H, d,J=5.0), 8.27 (1H, d, J=5.0)

Example 869 Compound AZ3 (2-Fluoropyridin-4-yl)2-methylpropionitrile

The title compound was prepared from (2-fluoropyridin-4-yl) acetonitrilein the same manner as the method for Compound K2.

¹H-NMR (270 MHz DMSO-d₆) δ: 1.72 (6H, s), 7.34 (1H, s), 7.53 (1H, d,J=5.3), 8.31 (1H, d, J=5.3)

Example 870 Compound AZ44-(2-Fluoropyridin-4-yl)-4-methyl-3-oxopentanoic Acid Ethyl Ester

The title compound was prepared from (2-fluoropyridin-4-yl)2-methylpropionitrile in the same manner as the method for Compound K3.

¹H-NMR (270 MHz DMSO-d₆) δ: 1.13 (3H, t, J=7.3), 1.48 (6H, s), 3.57 (2H,s), 4.01 (2H, q, J=7.3), 7.12 (1H, s), 7.25 (1H, d, J=5.3), 8.22 (1H, d,J=5.3)

Example 871 Compound AZ56-Cyano-2-[1-(2-fluoropyridin-4-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicAcid Ethyl Ester

The title compound was prepared from4-(2-fluoropyridin-4-yl)-4-methyl-3-oxopentanoic acid ethyl ester in thesame manner as the method for Compound K4 and Compound K5.

LCMS: m/z 352 [M+H]⁺

¹H-NMR (270 MHz DMSO-d₆) δ: 1.05 (3H, t, J=7.3), 1.82 (6H, s), 3.98 (2H,q, J=7.3), 6.99-7.02 (2H, m), 7.16 (1H, dd, J=8.4, 1.5), 7.97 (1H, s),8.05-8.11 (2H, m)

Example 872 Compound AZ66-Cyano-2-[1-(2-(4-morpholin-4-yl-piperidin-1-yl))pyridin-4-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicAcid Ethyl Ester

6-Cyano-2-[1-(2-fluoropyridin-4-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicacid ethyl ester (110 mg) was dissolved in NMP (3.3 ml), added with4-morpholin-4-yl-piperidine (319 mg), and stirred in a sealing tube at120° C. for 1 hr. The reaction mixture was diluted with ethyl acetate(50 ml) and washed with 15% brine and distilled water in order. Theorganic layer was concentrated and purified by silica gel column(DCM/methanol=20/1) to obtain the title compound (120 mg, 76%).

LCMS: m/z 502 [M+H]⁺

Example 873 Compound AZ7-15,5-Dimethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-pyrido[4,3-b]carbazole-8-carboxylic Acid Amide

6-Cyano-2-[1-(2-(4-morpholin-4-yl-piperidin-1-yl))pyridin-4-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicacid ethyl ester (110 mg) was dissolved in Eaton's reagent (2.5 ml) andstirred at 55° C. for 17 hrs. The reaction mixture was neutralized withsaturated aqueous solution of sodium bicarbonate. The precipitatedmatters were collected by filtration, and then washed with water toobtain the title compound (72 mg, 70%).

LCMS: m/z 474 [M+H]⁺

HPLC retention time: 1.17 min (analysis condition U)

¹H-NMR (270 MHz DMSO-d₆) δ: 1.38 (2H, m), 1.75 (6H, s), 1.88 (2H, m),2.44 (5H, m), 2.94 (2H, m), 3.57 (4H, m), 4.58 (2H, m), 7.10 (1H, s),7.32 (1H, s), 7.75 (1 H, d, J=8.4), 8.00 (2H, m), 8.15 (1H, d, J=8.4),8.85 (1H, s), 12.3 (1H, s)

Example 874 Compound AZ7-25,5-Dimethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-pyrido[4,3-b]carbazole-8-carbonitrile

5,5-Dimethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-pyrido[4,3-b]carbazole-8-carboxylicacid amide (54 mg) was dissolved in DMF (1 ml), added with thionylchloride (25 μL), and the mixture was stirred at room temperature for 1hr. The reaction mixture was diluted with water. The precipitatedmatters were collected by filtration to obtain the title compound (25mg, 49%).

LCMS: m/z 456 [M+H]⁺

HPLC retention time: 1.55 min (analysis condition U) ¹H-NMR (270 MHzDMSO-d₆) δ: 1.36 (2H, m), 1.76 (6H, s), 1.89 (2H, m), 2.44 (5H, m), 2.95(2H, m), 3.57 (4H, m) 4.58 (2H, m), 7.10 (1H, s), 7.59 (1H, d, J=8.0),7.99 (1H, s), 8.29 (1H, d, J=8.0), 8.86 (1H, s), 12.7 (1H, s)

The compounds described in the following Tables 12-13 were synthesizedby introducing a corresponding amino group to6-cyano-2-[1-(2-fluoropyridin-4-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicacid ethyl ester and forming a ring according to the method that is usedfor the synthesis of Compound AZ7-1. Furthermore, the preparation wascarried out by converting the substituent group at position 3 from acarboxamide group to a cyano group according to the method that is usedfor the synthesis of Compound AZ7-2.

TABLE 12 HPLC Reten- Example Comp. Con- tion No. No. Structure CompoundName dition Time m/z 875 AZ7-3

3-[4-((2R,6S)-2,6- Dimethyl-morpholine- 4-yl)-piperidine-1-yl]-5,5-dimethyl-11- oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8-carboxylic acid amide U 1.32 502 876 AZ7-4

3-[4-((2R,6S)-2,6- Dimethyl-morpholine- 4-yl)-piperidine-1-yl]-5,5-dimethyl-11- oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8-carbonitrile U 1.70 484 877 AZ7-5

3-[1,4′]Bipiperidinyl- 1′-yl-5,5-dimethyl- 11-oxo-6,11-dihydro-5H-pyrido[4,3- b]carbazole-8- carboxylic acid amide U 1.30 472 878 AZ7-6

5,5-Dimethyl-3-(4- methyl-4-morpholine- 4-yl-piperidine-1-yl)-11-oxo-6,11-dihydro- 5H-pyrido[4,3- b]carbazole-8- carboxylic acid amideY 1.00 488 879 AZ7-7

5,5-Dimethyl-3-(4- methyl-4-morpholine- yl-piperidine-1-yl)-11-oxo-6,11-dihydro- 5H-pyrido[4,3- b]carbazole-8- carbonitrile Y 1.62470 880 AZ7-8

3-(4-Cyclobutyl- piperazine-1-yl)-5,5- dimethyl-11-oxo- 6,11-dihydro-5H-pyrido[4,3- b]carbazole-8- carboxylic acid amide Y 1.22 444 881 AZ7-9

3-(4-Cyclobutyl- piperazine-1-y)-5,5- dimethyl-11-oxo- 6,11-dihydro-5H-pyrido[4,3- b]carbazole-8- carbonitrile Y 1.55 426 882 AZ7-10

3-[1,4′]Bipiperidinyl- 1′-yl-5,5-dimethyl- 11-oxo-6,11-dihydro-5H-pyrido[4,3- b]carbazole-8- carbonitrile Y 1.73 454 883 AZ7-11

5.5-Dimethyl-3- morpholine-4-yl-11- oxo-6,11-dihydro-5H- pyrido[4,3-b]carbazole-8- carboxylic acid amide U 1.33 391 884 AZ7-12

5,5-Dimethyl-3- morpholine-4-yl-11- oxo-6,11-dihydro-5H- pyrido[4,3-b]carbazole-8- carbonitrile U 1.77 373 885 AZ7-13

3-[4-(1-Ethyl- cyclobutyl)- piperazine-1-yl]-5,5- dimethyl-11-oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carbonitrile Y 1.93 464 886AZ7-14

3-(4-Ethyl-4- morpholine-4-yl- piperidine-1-yl)-5,5- dimethyl-11-oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acid amide Y 1.18502 887 AZ7-15

3-(4-Ethyl-4- morpholine-4-yl- piperidine-1-yl)-5,5- dimethyl-11-oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carbonitrile Y 1.78 484 888AZ7-16

3-[4-(1-Ethyl- cyclobutyl)- piperazine-1-yl]-5,5- dimetbyl-11-oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acid amide Y 1.25472

TABLE 13 HPLC Reten- Example Comp. Con- tion No. No. Structure CompoundName dition Time m/z 889 AZ7-17

3-(4-Isopropyl- 4-morpholine-4- yl-piperidine-1- yl)-5,5-dimethyl-11-oxo-6,11- dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acidamide U 1.27 516 890 AZ7-18

5,5-Dimethyl-3- (4-morpholine-4- yl-4-propyl- piperidine-1-yl)-11-oxo-6,11- dihydro-5H- pyrido[4.3- b]carbazole-8- carboxylic acidamide U 1.36 516 891 AZ7-19

5,5-Dimethyl-3- (4-morpholine-4- yl-4-propyl- piperidine-1-yl)-11-oxo-6,11- dihydro-5H- pyrido[4,3- b]carbazole-8- carbonitrile U 1.68498 892 AZ7-20

3-(4-isopropyl- 4-morpholine-4- yl-piperidine-1- yl)-5,5-dimethyl-11-oxo-6,11- dihydro-5H- pyrido[4,3- b]carbazole-8- carbonitrile U 1.60498 893 AZ7-21

5,5-Dimethyl- 11-oxo-3-[4-(1- propyl- cyclobutyl)- piperazine-1-yl]-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acid amide U 1.58486 894 AZ7-22

5,5-Dimethyl- 11-oxo-3-[4-(1- propyl- cyclobutyl)- piperazine-1-yl]-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carbonitrile U 1.97 468

The compounds described in the following Table 14 were synthesized from(2-chloro-3-fluoropyridin-4-yl)methanol according to the method that isused for the synthesis of Compound AZ1 to AZ7-2.

TABLE 14 HPLC Reten- Example Comp. Con- tion No. No. Structure CompoundName dition Time m/z 895 AZ7-23

4-Fluoro-5,5- dimethyl-3-(4- morpholine-4-yl- piperidine-1-yl)-11-oxo-6,11-dihydro- 5H-pyrido[4,3- b]carbazole-8- carboxylic acid amide U1.37 492 896 AZ7-24

4-Fluoro-5,5- dimethyl-3-(4- morpholin-4-yl- piperidin-1-yl)-11-oxo-6,11-dihydro- 5H-pyrido[4,3- b]carbazole-8- carbonitrile U 1.74 474897 AZ7-25

4-Fluoro-5,5- dimethyl-11-oxo-3- [4-(3-oxo- piperazin-1-yl)-piperidin-1-yl]-6,11- dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylicacid amide U 1.32 505 898 AZ7-26

3- [1,4′]Bipiperidinyl- 1′-yl-4-fluoro-5,5- dimethyl-11-oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carboxylic acid amide U 1.45490 899 AZ7-27

3- [1,4′]Bipiperidinyl- 1′-yl-4-fluoro-5,5- dimethyl-11-oxo-6,11-dihydro-5H- pyrido[4,3- b]carbazole-8- carbonitrile U 1.87 472

Example 900 Compound BZ1 2-Cyano-4-hydrazinopyridine

4-Chloro-2-cyanopyridine (1 g) was dissolved in hydrazine monohydrate (1ml) and 1,4-dioxane (10 ml), and stirred overnight under reflux. Thereaction solution was diluted with water (30 ml) and extractedrepeatedly with ethyl acetate. The organic layer was concentrated toobtain the title compound as a crude product, which was used for thenext step without further purification.

LCMS: m/z 135 [M+H]⁺

Example 901 Compound BZ2-18-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[f]pyrido[4,3-b]indol-3-carbonitrile

According to the method used for synthesizing Compound A3-1, theintermediate was prepared from 2-cyano-4-hydrazinopyridine and7-methoxy-1,1-dimethyl-3,4 dihydro-1H-naphthalen-2-one. Without anypurification, the intermediate was subjected to oxidation according tothe method used for synthesizing Compound A4 to obtain the titlecompound.

LCMS: m/z 318 [M+H]⁺

HPLC retention time: 2.10 min (analysis condition U)

Example 902 Compound BZ2-23-Chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[f]pyrido[4,3-b]indol-11-one

According to the method used for synthesizing Compound A3-1, theintermediate was prepared from 2-chloro-4-hydrazinopyridine and7-methoxy-1,1-dimethyl-3,4 dihydro-1H-naphthalen-2-one. Without anypurification, the intermediate was subjected to oxidation according tothe method used for synthesizing Compound A4 to obtain the titlecompound.

LCMS: m/z 327, 329 [M+H]⁺

HPLC retention time: 1.80 min (analysis condition S)

Example 903 Compound CZ12-Bromo-8-methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one

According to the method used for synthesizing Compound A3-1, theintermediate was prepared from 2-bromo-6-hydrazinopyridine and7-methoxy-1,1-dimethyl-3,4 dihydro-1H-naphthalen-2-one. Without anypurification, the intermediate was subjected to oxidation according tothe method used for synthesizing Compound A4 to obtain the titlecompound.

LCMS: m/z 371, 373 [M+H]⁺

HPLC retention time: 2.85 min (analysis condition U)

Example 904 Compound CZ28-Methoxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile

According to the method 1 for Compound A5-2,2-bromo-8-methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-onewas subjected to cyanation to obtain the title compound.

LCMS: m/z 318 [M+H]⁺

HPLC retention time: 2.35 min (analysis condition U)

Example 905 Compound CZ38-Hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile

According to the method used for synthesizing Compound A6,8-methoxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrilewas subjected to demethylation to obtain the title compound.

LCMS: m/z 304 [M+H]⁺

HPLC retention time: 1.72 min (analysis condition S)

Example 906 Compound CZ4 Trifuloromethanesulfonic Acid2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-ylEster

According to the method used for synthesizing Compound B1,8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrilewas subjected to trifluoromethanesulfone esterification to obtain thetitle compound.

LCMS: m/z 436 [M+H]⁺

HPLC retention time: 3.32 min (analysis condition Y)

Example 907 Compound CZ5-110,10-Dimethyl-5-oxo-8-piperazin-1-yl-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile

According to the method used for synthesizing Compound B2-1,trifluoromethanesulfonic acid2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-ylester was introduced with piperazine to obtain the title compound.

LCMS: m/z 372 [M+H]⁺

HPLC retention time: 1.17 min (analysis condition S)

Example 908 Compound CZ5-210,10-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile

According to the method used for synthesizing Compound B2-1,trifluoromethanesulfonic acid2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-ylester was introduced with 4-morpholin-4-yl piperidine to obtain thetitle compound.

LCMS: m/z 456 [M+H]⁺

HPLC retention time: 1.68 min (analysis condition U)

Example 909 Compound CZ68-(4-Cyclobutyl-piperazin-1-yl)-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile

According to the method used for synthesizing Compound B3-32,10,10-dimethyl-5-oxo-8-piperazin-1-yl-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrilewas subjected to reductive amination with cyclobutanone to obtain thetitle compound.

LCMS: m/z 426 [M+H]⁺

HPLC retention time: 1.60 min (analysis condition U)

Example 910 Compound DZ16-Ethynyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (1 g) wasdissolved in acetonitrile (50 ml), added with PdCl₂(CH₃CN)₂ (45 mg),X-phos (168 mg), CsCO₃ (1.2 g) and trimethylsilylacetylene (0.9 ml), andthe mixture was stirred at 85° C. for 2 hrs. The reaction mixture wasdiluted with ethyl acetate (100 ml). The organic layer was washed twicewith 10% brine and concentrated under reduced pressure. The resultingresidues were dissolved in THF (10 ml), added with the THF solution (4ml) comprising tetrabutylammonium fluoride and stirred at roomtemperature for 1 hr. The reaction mixture was diluted with ethylacetate (100 ml). The organic layer was washed twice with 10% brine andconcentrated under reduced pressure. The resulting residues werepurified by silica gel column (n-hexane/ethyl acetate=9/1) to obtain thetitle compound (346 mg, two step yield 43%).

LCMS: m/z 229 [M+H]⁺

Example 911 Compound DZ26-Ethyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

6-Ethynyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (346mg) was dissolved in ethanol:THF (=2:1 mixture solvent, 20 ml), addedwith 10% Pd/C (170 mg), and then the mixture was stirred at roomtemperature for 1 hr under hydrogen atmosphere. The catalyst was removedby filtration and the organic layer was concentrated under reducedpressure to obtain the title compound (322 mg, yield 91%).

LCMS: m/z 233 [M+H]⁺

Example 912 Compound DZ32-Bromo-7-ethyl-8-methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one

According to the method used for synthesizing Compound A3-1, theintermediate was prepared from 2-bromo-6-hydrazinopyridine and6-ethyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one. Withoutany purification, the intermediate was subjected to oxidation accordingto the method used for synthesizing Compound A4 to obtain the titlecompound.

LCMS: m/z 399, 401 [M+H]⁺

HPLC retention time: 3.35 min (analysis condition Y)

Example 913 Compound DZ47-Ethyl-8-methoxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile

According to the method 1 for Compound A5-2,2-bromo-7-ethyl-8-methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-onewas subjected to cyanation to obtain the title compound.

LCMS: m/z 346 [M+H]⁺

HPLC retention time: 3.05 min (analysis condition Y)

Example 914 Compound DZ57-Ethyl-8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile

According to the method used for synthesizing Compound A5,7-ethyl-8-methoxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrilewas subjected to demethylation to obtain the title compound.

LCMS: m/z 332 [M+H]⁺

HPLC retention time: 2.60 min (analysis condition Y)

Example 915 Compound DZ6-1 Trifuloro-Methanesulfonic Acid2-cyano-7-ethyl-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-ylEster

According to the method used for synthesizing Compound B1,7-ethyl-8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrilewas subjected to trifluoromethanesulfone esterification to obtain thetitle compound.

LCMS: m/z 464 [M+H]⁺

HPLC retention time: 3.50 min (analysis condition Y)

The compounds described in the following Table 15 were prepared fromtrifluoro-methanesulfonic acid2-cyano-7-ethyl-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-ylester and corresponding amine according to the method that is used forthe synthesis of Compound B2-10. The compounds of Example 919 andExample 920 were obtained as a by-product of the reaction.

TABLE 15 HPLC Reten- Example Comp. Con- tion No. No. Structure CompoundName dition Time m/z 916 DZ7-1

6-(4-Cyclobutyl- piperazine-1-yl)-7-ethyl- 10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11- diaza-benzo[b]fluorene- 2-carbonitrile Y 1.83 454917 DZ7-2

7-Ethyl-10,10-dimethyl- 8-(4-morpholine-4-yl- piperidine-1-yl)-5-oxo-10,11-dihydro-5H-1,11- diaza-benzo[b]fluorene- 2-carbontrile Y 1.85 484918 DZ7-3

7-Ethyl-10,10-dimethyl- 8-morpholine-4-yl-5- oxo-10,11-dihydro-5H-1,11-diaza- benzo[b]fluorene-2- carbonitrile Y 3.0.2 401 919 DZ7-4

7-Ethy-10,10-dimethyl- 5-oxo-10,11-dihydro-5H- 1,11-diaza-benzo[b]fluorene-2- carbonitrile Y 3.07 316 920 DZ7-5

7-Ethy-10,10-dimethyl- 2-(morpholine-4- carbonyl)-8-morpholine-4-yl-10,11-dihydro-1,11- diaza-benzo[b]fluorene- 5-one Y 2.70 489

Example 921 Compound DZ6-28-(2-Diethylamino-ethoxy)-11-(2-diethylamino-ethyl)-7-ethyl-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile

According to the method used for synthesizing Compound A7-17,7-ethyl-8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrilewas alkylated to obtain the title compound.

LCMS: m/z 530 [M+H]⁺

HPLC retention time: 1.38 min (analysis condition Y)

Example 922 Compound EZ1 2-(6-Methoxy-pyridin-2-yl)-2-methyl-propionicAcid Ethyl Ester

2-Bromo-6-methoxypyridine (7.0 g), ethyl isobutyrate (4.75 g), trit-butylphosphine (300 mg) and Pd₂(dba)₃ (680 mg) were dissolved intoluene (200 ml) under nitrogen atmosphere, added with THF solution ofLiHMDS (1.6 M, 24 ml), and the mixture was stirred at 100° C. for 6 hrs.The reaction mixture was diluted with ethyl acetate (300 ml), and washedthree times with 15% brine (200 ml). The organic layer was concentratedunder reduced pressure and the resulting residues were purified bysilica gel column (n-hexane/ethyl acetate=4/1) to obtain the titlecompound (5.353 g, yield 60%).

LCMS: m/z 224 [M+H]⁺

Example 923 Compound EZ2 2-(6-Methoxy-pyridin-2-yl)-2-methyl-propionicAcid

2-(6-Methoxy-pyridin-2-yl)-2-methyl-propionic acid ethyl ester (5.33 g)was dissolved in methanol (200 ml), added with 5 N aqueous solution ofpotassium hydroxide (25 ml), and then stirred under reflux. The reactionmixture was concentrated and neutralized with 2 N hydrochloric acid. Theprecipitated matters were collected by filtration and dried to obtainthe title compound (3.55 g).

LCMS: m/z 196 [M+H]⁺

Example 924 Compound EZ34-(6-Methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butylester

The title compound was synthesized from2-(6-methoxy-pyridin-2-yl)-2-methyl-propionic acid and mono-tert-butylmalonic acid according to the method used for the synthesis of CompoundPR4. The resultant was used for the next step without furtherpurification.

Example 925 Compound EZ4-16-Cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicAcid Tert-Butyl Ester

According to the method that is used for the preparation of CompoundPR5-1, the title compound was synthesized from4-(6-methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butylester and 4-chloro-3-nitrobenzonitrile

LCMS: m/z 392 [M+H]⁺

Example 926 Compound EZ4-26-Cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-benzofuran-3-carboxylicAcid Tert-Butyl Ester

According to the method that is used for the preparation of CompoundFR1, the title compound was synthesized from4-(6-methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butylester and 4-chloro-3-nitrobenzonitrile.

LCMS: m/z 393 [M+H]⁺

Example 927 Compound EZ5-16-Cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicAcid

According to the method that is used for the preparation of CompoundPR7, the title compound was synthesized from6-cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicacid tert-butyl ester.

LCMS: m/z 336 [M+H]⁺

Example 928 Compound EZ5-26-Cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-benzofuran-3-carboxylicacid

According to the method that is used for the preparation of CompoundPR7, the title compound was synthesized from6-cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-benzofuran-3-carboxylicacid tert-butyl ester.

LCMS: m/z 337 [M+H]⁺

Example 929 Compound EZ6-12-Methoxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-carboxylic Acid Amide

According to the method that is used for the preparation of CompoundAZ7-1, the title compound was synthesized from6-cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-1H-indole-3-carboxylicacid.

LCMS: m/z 336 [M+H]⁺

HPLC retention time: 1.98 min (analysis condition S)

Example 930 Compound EZ6-22-Methoxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5] furo[3,2-g]quinoline-8-carboxylic Acid Amide

According to the method that is used for the preparation of CompoundAZ7-1, the title compound was synthesized from6-cyano-2-[1-(6-methoxy-pyridin-2-yl)-1-methyl-ethyl]-benzofuran-3-carboxylicacid.

LCMS: m/z 337 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition S)

Example 931 Compound EZ7-12-Methoxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-carbonitrile

According to the method that is used for the preparation of CompoundAZ7-2, the title compound was synthesized from2-methoxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-carboxylicacid amide.

LCMS: m/z 318 [M+H]⁺

HPLC retention time: 2.60 min (analysis condition S)

Example 932 Compound EZ7-22-Methoxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5] furo[3,2-g]quinoline-8-carbonitrile

According to the method that is used for the preparation of CompoundAZ7-2, the title compound was synthesized from2-methoxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinoline-8-carboxylicacid amide.

LCMS: m/z 319 [M+H]⁺

HPLC retention time: 3.18 min (analysis condition S)

Example 933 Compound EZ8-12-Hydroxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-carbonitrile

According to the method that is used for the preparation of Compound A5,2-methoxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-carbonitrile was demethylated to synthesize the titlecompound.

LCMS: m/z 304 [M+H]⁺

HPLC retention time: 1.70 min (analysis condition U)

Example 934 Compound EZ8-22-Hydroxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinoline-8-carbonitrile

According to the method that is used for the preparation of Compound A5,2-methoxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinoline-8-carbonitrile was demethylated to synthesize the titlecompound.

LCMS: m/z 305 [M+H]⁺

HPLC retention time: 2.17 min (analysis condition U)

The compounds described in the following Table 16 were synthesized from2-hydroxy-11,11-dimethyl-5-oxo-10,11-dihydro-5H-pyrido[2,3-b]carbazole-8-carbonitrile or from2-hydroxy-11,11-dimethyl-5-oxo-5,11-dihydro-benzo[4,5]furo[3,2-g]quinoline-8-carbonitrileaccording to the method described in the Table.

TABLE 16 HPLC Reten- Example Comp. Con- tion No. No. Structure CompoundName dition Time m/z Method 935 EZ9-1

Trifluoro- methanesulfonic acid 8-cyano- 11,11-dimethyl-5- oxo-10,11-dihydro-5H- pyrido[2,3- b]carbazol-2-yl ester U 2.93 436 B1 936 EZ9-2

11,11-Dimethyl- 5-oxo-2- (tetrahydro-pyran- 4-yloxy)-10,11- dihydro-5H-pyrido[2,3- b]carbazole-8- carbonitrile U 2.57 388 A7-1 937 EZ9-3

2-(2- Diethylamino- ethoxy)-11,11- dimethyl-5-oxo- 10,11-dihydro-5H-pyrido[2,3- b]carbazole-8- carbonitrile Y 1.63 403 A7-17 938 EZ9-4

2-(2- Diethylamino- ethoxy)-10-(2- diethylamino- ethyl)-11,11-dimethyl-5-oxo- 10,11-dihydro-5H- pyrido[2,3- b]carbazole-8-carbonitrile Y 1.82 502 A7-17 939 EZ9-5

2-(2- Diethylamino- ethoxy)-11,11- dimethyl-5-oxo- 5,11-dihydro-benzo[4,5]furo[3,2- g]quinoline-8- carbonitrile Y 1.77 404 A7-17

The compounds described in the following Table 17 were synthesized fromCompound W3 and corresponding halide by alkylation of hydroxyl groupaccording to the method that is used for the synthesis of CompoundA7-17.

TABLE 17 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 940 W4-3

7-(2-Dimethylamino- ethoxy)-6,6-dimethyl- 11-oxo-6,11-dihydro-5H-benzo[b]carbazole- 3-carbonitrile I 0.96 374.0 941 W4-4

7-(3-Dimethylamino- propoxy)-6,6-dimethyl- 11-oxo-6,11-dihydro-5H-benzo[b]carbazole- 3-carbonitrile I 0.92 338.0

The compounds described in the following Table 18 were synthesizedaccording to the method shown below. Specifically, Compound GT1-1 wasprepared from Compound J2 and phenylhydrazine according to the methodthat is used for the synthesis of Compound A3 and Compound A4.Subsequently, in accordance with the methylation carried out in the samemanner as Compound A10-1, Compound GT1-2 was prepared.

TABLE 18 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 942 GT1-1

9-Methoxy-6,6- dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A 2.36292.0 A3 A4 943 GT1-2

9-Methoxy-5,6,6- trimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A 2.53306.0 A10-1

The compounds described in the following Table 19 were synthesizedaccording to the method shown below. Specifically, Compound GT2-1 wasprepared from Compound A2 and phenylhydrazine according to the methodthat is used for the synthesis of Compound A3 and Compound A4.

Subsequently, by carrying out the alkylation in the same manner asCompound A10-1, Compound GT2-2 and Compound GT2-8 were prepared.

To obtain the compounds of the Table, chemical conversion of CompoundGT2-1 or the 5-alkylate of Compound GT2-1 was achieved by using incombination the functional group modifications (e.g., demethylationaccording to the method used for the preparation of Compound A6 andsubsequent introduction of a functional group, etc.) as explained beforeand described in the Table.

TABLE 19 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z Method 944 GT2-1

8-Methoxy-6,6- dimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A 2.30292.0 A3 A4 945 GT2-2

8-Methoxy-5,6,6- trimethyl-5,6 dihydro- benzo[b]carbazol- 11-one A 2.55306.0 A10-1 946 GT2-3

8-(2- Diethylamino- ethoxy)-5,6,6- trimethyl-5,6- dihydro-benzo[b]carbazol- 11-one A 1.90 391.0 A6 A7-17 A10-1 947 GT2-4

8-((R)-2,3- Dihydroxy- propoxy)-5,6,6- trimethyl-5,6- dihydro-benzo[b]carbazol- 11-one A 1.90 366.0 A6 A7-17 A10-1 948 GT2-5

8-(2- Diethylamino- ethoxy)-6,6- dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one F 1.93 377.3 A6 A7-17 949 GT2-6

8-(2- Diethylamino- ethoxy)-6,6- dimethyl-5- propyl-5,6- dihydro-benzo[b]carbazol- 11-one A 2.09 419.0 A6 A7-17 A10-1 950 GT2-7

5-Benzyl-8-(2- diethylamino- ethoxy)-(6,6- dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one B 4.83 467.3 A6 A7-17 A10-1 951 GT2-8

5-Ethyl-8- methoxy-6,6- dimethyl-5,6- dihydro- benzo[b]carbazol- 11-oneF 2.94 320.0 A10-1 952 GT2-9

8-(2- Diethylamino- ethoxy)-5-ethyl- 6,6-dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one F 2.16 405.0 A6 A7-17 A10-1 953 GT2-10

8-(2- Diethylamino- ethoxy)-5- isopropyl-6,6- dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one A 2.02 419.0 A6 A7-17 A10-1 954 GT2-11

8-((R)-2,3- Dihydroxy- propoxy)-6,6- dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one C 2.17 352.2 A6 A7-17 A7-14-2 955 GT2-12

5- Methanesulfonyl- 8-methoxy-6,6- dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one C 2.87 370.1 A9-1 956 GT2-13

8-(2- Diethylamino- ethoxy)-5- methanesulfonyl- 6,6-dimethyl-5,6-dihydro- benzo[b]carbazol- 11-one F 2.20 455.1 A6 A7-17 A9-1 957 GT2-14

8-(2- Diethylamino- ethoxy)-5-(2- hydroxy-ethyl)- 6,6-dimethyl-5,6-dihydro- benzo[b]carbazol- 11-one H 3.73 421.0 A.6 A7-17 A10-1 958GT2-15

6,6-Dimethyl-8- ((2R,3R)-2,3,4- trihydroxy- butoxy)-5,6- dihydro-benzo[b]carbazol- 11-one H 3.73 332.4 A7-1 A7-14-2

The compounds described in the following Table 20 were synthesizedaccording to the method shown below. Specifically, by using Compound A2and phenylhydrazine having a corresponding substituent group, 2 (or3)-substituted-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-11-onewas prepared according to the method that is used for the synthesis ofCompound A3 and Compound A4. Subsequently, to obtain the compounds ofthe Table, chemical conversion of the above compounds was achieved byusing in combination the functional group modifications as explainedbefore and described in the Table.

TABLE 20 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z Method 959 GT3-1

8-Methoxy-3,6,6- trimethyl-5,6- dihydro- benzo[b]carbazol- 11-one A 2.39306.0 A3 A4 960 GT3-2

8-(2-Diethylamino- ethoxy)-3,5,6,6- tetramethyl-5,6- dihydro-benzo[b]carbazol- 11-one A 1.97 405.0 A6 A7-17 A10-1 961 GT3-3

8-(2-Diethylamino- ethoxy)-6,6- dimethyl-3-nitro- 5,6-dihydro-benzo[b]carbazol- 11-one B 3.86 422.2 A6 A7-17 962 GT3-4

8-(2-Diethylamino- ethoxy)-6,6- dimethyl-3- trifluoromethyl-5,6-dihydro- benzo[b]carbazol- 11-one A 2.03 445.0 A6 A7-17 963 GT3-5

8-(2-Diethylamino- ethoxy)-5-(2- diethylamino- ethyl)-6,6-dimethyl-3-nitro- 5,6-dihydro- benzo[b]carbazol- 11-one F 1.74 521.3 A6A7-17 A10-1 964 GT3-6

2,6,6-Trimethyl-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)- 5,6-dihydro-benzo[b]carbazol- 11-one F 2.03 396.0 A6 A7-17 A7-14- 2 965 GT3-7

2-Fluoro-6,6- dimethyl-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-5,6-dihydro- benzo[b]carbazol- 11-one F 1.99 400.0 A6 A7-17 A7-14- 2 966GT3-8

2-Chloro-6,6- dimethyl-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-5,6-dihydro- benzo[b]carbazol- 11-one F 2.14 416.0 A6 A7-17 A7-14- 2 967GT3-9

6,6-Dimethyl-11- oxo-8-((2R,3R)- 2,3,4-trihydroxy- butoxy)-6,11-dihydro-5H- benzo[b]carbazole- 2-carbonitrile F 1.90 407.4 A6 A7-17A7-14- 2 968 GT3- 10

6,6-Dimethyl-3- trifluoromethoxy-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-5,6-dihydro- benzo[b]carbazol- 11-one F 2.31 466.4 A6 A7-17 A7-14- 2 969GT3- 11

8-((R)-2,3- Dihydroxy- propoxy)-6,6- dimethyl-3- trifluoromethoxy-5,6-dihydro- benzo[b]carbazol- 11-one F 2.43 436.4 A6 A7-17 A7-14- 2 970GT3- 12

8-((R)-2,3- Dihydroxy- propoxy)-3- methoxy-5,6,6- trimethyl-5,6-dihydro- benzo[b]carbazol- 11-one B 3.79 396.5 A6 A7-17 A10-1 A7-14- 2971 GT3- 13

8-((R)-2,3- Dihydroxy- propoxy)-3- methoxy-6,6- dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one B 3.40 382.4 A6 A7-17 A7-14- 2

The compounds described in the following Table 21 were synthesizedaccording to the method shown below. Specifically, by using Compound E1and phenylhydrazine having a corresponding substituent group,9-bromo-1-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-oneor9-bromo-8-methoxy-6,6-dimethyl-3-trifluoromethoxy-5,6-dihydro-benzo[b]carbazol-11-onewas prepared according to the method used for the synthesis of CompoundA3 and Compound A4. Subsequently, to obtain the compounds of the Table,chemical conversion of the above compounds was achieved by using incombination the functional group modifications as explained before anddescribed in the Table.

TABLE 21 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z Method 972 GT4-1

9-Bromo-8-((R)- 2,3-dihydroxy- propoxy)-6,6- dimethyl-3-trifluoromethoxy- 5,6-dihydro- benzo[b]carbazol- 11-one C 2.68 514.0 A6A7-17 A7-14-2 973 GT4-2

9-Bromo-1- chloro-8-((R)-2,3- dihydroxy- propoxy)-6,6- dimethyl-5,6-dihydro- benzo[b]carbazol- 11-one C 2.58 464.0 A6 A7-17 A7-14-2

The compounds described in the following Tables 22-23 were synthesizedaccording to the method shown below. Specifically, catalytic reductionof Compound GT3-3 was carried out according to the method used for thepreparation of Compound D2 to prepare Compound GT5-1.

Reductive alkylation of Compound GT5-1 was carried out according to themethod used for the preparation of Compound B3-32 for the introductionof a methyl group or a benzyl group (Compound GT5-2, Compound GT5-3).

Catalytic reduction of Compound GT5-3 was carried out according to themethod used for the preparation of Compound D2, and then processed toprepare Compound GT5-4.

The resulting amino derivatives of Compound GT5-1 to 4 were reacted withcorresponding acyl chloride, isocynate, or chloroformate according tothe method used for the preparation of Compound A9-1 to obtain thecompounds of the Table.

TABLE 22 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z Method 974 GT5-1

3-Amino-8-(2- diethylamino- ethoxy)-6,6- dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one A 1.15 392.3 D2 975 GT5-2

8-(2-Diethylamino- ethoxy)-3- dimethylamino-6,6- dimethyl-5,6- dihydro-benzo[b]carbazol- 11-one A 1.18 420.2 B3-32 976 GT5-3

3-(Benzyl-methyl- amino)-8-(2- diethylamino- ethoxy)-6,6- dimethyl-5,6-dihydro- benzo[b]carbazol- 11-one B 3.05 496.4 B3-32 977 GT5-4

8-(2-Diethylamino- ethoxy)-6,6- dimethyl-3- methylamino-5,6- dihydro-benzo[b]carbazol- 11-one B 2.46 406.3 B3-32 D2 978 GT5-5

Pentanoic acid [8- (2-diethylamino- ethoxy)-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazol- 3-yl]amide C 2.52 476.5 A9-1 979GT5-6

N-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-2,2-dimethyl- propionamide A 1.74 476.4 A9-1 980GT5-7

[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-carbamic acid 2-methoxy-ethyl A 1.55 494.3 A9-1ester 981 GT5-8

1-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-3-phenyl-urea B 3.79 511.3 A9-1 982 GT5-9

N-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-2-phenyl- acetamide B 3.81 510.4 A9-1 983 GT5-10

N-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-3- trifluoromethyl- benzamide B 4.47 564.4 A9-1984 GT5-11

1-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-3-(3- trifluoromethyl- phenyl)-urea B 4.55 579.4A9-1 985 GT5-12

[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-carbamic acid 3-trifluoromethyl- H 5.17 580.1A9-1 phenyl ester 986 GT5-13

N-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-2-phenoxy- acetamide C 2.57 526.1 A9-1 987GT5-14

1-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-1-methyl-3- phenyl-urea B 3.83 525.6 A9-1

TABLE 23 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z Method 988 GT5-15

1-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-1-methyl-3- (3-trifluoromethyl- phenyl)-urea B4.58 593.4 A9-1 989 GT5-16

3-Benzyl-1-[8-(2- diethylamino- ethoxy)-6,6- dimethyl-11-oxo-6,11-dihydro-5H- benzo[b]carbazol- 3-yl]-1-methyl- urea B 3.81 539.4A9-1 990 GT5-17

N-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]N-methyl-3- trifluoromethyl- benzamide B 4.15578.3 A9-1 991 GT5-18

N-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]N-methyl-2- phenoxy- acetamide C 2.62 540.4 A9-1992 GT5-19

3-(4-tert-Butyl- phenyl)-1-[8-(2- diethylamino- ethoxy)-6,6-dimethyl-11-oxo- 6,11-dihydro-5H- benzo[b]carbazol- 3-yl]-1-methyl- ureaF 2.45 581.6 A9-1 993 GT5-20

1-[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]-3-(4- methoxy-phenyl)- 1-methyl-urea B 3.77555.4 A9-1 994 GT5-21

[8-(2- Diethylamino- ethoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazol- 3-yl]carbamic acid phenyl ester A 1.89 512.2 A9-1

The compounds described in the following Table 24 were synthesizedaccording to the method shown below. Specifically, having Compound T22-1as a starting material,8-[(4R,5R)-5-(tert-butyl-dimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-5,6-dihydro-11-oxo-benzo[b]carbazole-3-carboxylicacid was prepared according to the method that is used for thepreparation of Compound B2-28.

The resulting carboxylic acid was subjected to dehydrating condensationwith corresponding amine, alcohol according to the method that is usedfor the preparation of Compound A9-10. Subsequently, deprotection wascarried out according to the method used for the preparation of CompoundT22-1-1 and Compound T22-1-2 to obtain the compounds described in theTable.

TABLE 24 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z Method  995 GT6-1

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid phenylamide A 1.79 501.0A8-10  996 GT6-2

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid dimethylamide D 1.33453.0 A9-10  997 GT6-3

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid 2-hydroxy-ethyl ester A1.40 470.0 A9-10  998 GT6-4

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid butylamide D 1.55 481.0A9-10  999 GT6-5

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid (2-methoxy-ethyl)- amideD 1.30 483.0 A9-10 1000 GT6-6

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid methylamide D 1.24 439.0A9-10 1001 GT6-7

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid benzylamide D 1.58 515.0A9-10 1002 GT6-8

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid amide D 1.18 425.0 A9-101003 GT6-9

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid pyridin-4-ylamide D 1.40502.0 A9-10 1004 GT6-10

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carbolic acid D 1.01 426.0 E2-28 1005GT6-11

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid pyridin-2-ylamide D 1.52502.0 A9-10 1006 GT6-12

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid pyridin-3-ylamide D 1.34502.0 A9-10 1007 GT6-13

6,6-Dimethyl-11-oxo-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carboxylic acid phenethyl-amide D 1.67529.0 A9-10 1008 GT6-14

N-[6,6-Dimethyl-11- oxo-8-((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b] carbazole-3-carbonyl]- benzenesulfonamide D 1.23565.0 A9-10

To the compounds described in the following Table 25, a hydroxyl groupwas introduced from Compound T17-3 according to the method described inJACS 2006, Vol. 128, page 10964. Subsequently, deprotection was carriedout according to the method used for Compound A7-14-2 and Compound T22-2to obtain the compounds shown below.

TABLE 25 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z 1009 GT7-1

8-((R)-2,3-Dihydroxy- propoxy)-3- hydroxy-6,6-dimethyl- 5,6-dihydro-benzo[b]carbazol-11-one B 2.59 368.4 1010 GT7-2

8-((R)-2,3-Dihydroxy- propoxy)-3- hydroxy-5,6,6-trimethyl- 5,6-dihydro-benzo[b]carbazol-11-one C 1.90 382.4

The compounds described in the following Table 26 were prepared byalkylation according to the method used for the preparation of CompoundA7-1 from Compound GT7-1 or Compound GT7-2, or by carbamation accordingto the method used for the preparation of A9-1.

TABLE 26 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z Method 1011 GT8-1

8-((R)-2,3- Dihydroxy-propoxy)- 3-ethoxy- 5,6,6-trimethyl- 5,6-dihydro-benzo[b]carbazol- 11-one C 2.43 410.5 A7-1 1012 GT8-2

8-((R)-2,3- Dihydroxy- propoxy)-3- ethoxy-6,6-dimethyl- 5,6-dihydro-benzo[b]carbazol- 11-one C 2.30 386.5 A7-1 1013 GT8-3

8-((R)-2,3- Dihydroxy- propoxy)-5,6,6- trimethyl-3-(oxetan-3-yloxy)-5,6- dihydro-benzo[b] carbazol- 11-one B 1.72 438.5 A7-1 1014GT8-4

Phenyl-carbamic acid 8-((R)- 2,3-dihydroxy- propoxy)-6,6- dimethyl-11-oxo-6,11- dihydro-5H- benzo[b]carbazol- 3-yl ester E 4.23 487.0 A8-1

Example 1015 Compound GT9-18-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-3-(2H-tetrazol-5-yl)-5,6-dihydro-benzo[b]carbazol-11-one

8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile(20.0 mg, 0.048 mmol), ammonium chloride (1.28 mg, 0.024 mmol) and NaN₃(6.24 mg, 0.096 mmol) were dissolved in DMF, and the mixture was stirredat 120° C. for 14 hrs. NaN₃ (6.24 mg, 0.096 mmol) was further added tothe mixture, which was then stirred at 120° C. for 30 hrs. The reactionsolution was added with 1 N aqueous solution of hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and concentrated under reduced pressure. The resultantsolid obtained after concentration was washed with hexane:ethylacetate=1:1 to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-3-(2H-tetrazol-5-yl)-5,6-dihydro-benzo[b]carbazol-11-oneas a white solid.

The product was suspended in MeOH (1.0 ml), added with 1 N aqueoussolution of hydrochloric acid, and then stirred at 60° C. for 1 hr and30 min. After cooling to room temperature, the reaction solution wasconcentrated under reduced pressure, and the resulting solid was washedwith DCM to obtain the title compound as a pale yellow solid (13.4 mg,66.3%).

LCMS: m/z 420 [M+H]⁺

Example 1016 Compound GT9-28-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-3-thiophen-3-yl-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (20.0 mg,0.043 mmol), thiophene-3-boronic acid (10.9 mg, 0.085 mmol), K₃PO₄ (40mg) and Pd (PPh₃)₄ (9.9 mg, 0.0086 mmol) were dissolved in DMA (0.8 ml)and water (0.2 ml), and stirred at 140° C. for 10 min under microwaveirradiation. The reaction solution was diluted with ethyl acetate andwashed with saturated brine. The organic layer was concentrated underreduced pressure, and the resulting residues were purified by columnchromatography (hexane/ethyl acetate) to obtain8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-3-thiphen-3-yl-5,6-dihydro-benzo[b]carbazol-11-one.

This product was suspended in MeOH (1.0 ml), added with 1 N hydrochloricacid, and then stirred at 60° C. for 1 hr and 30 min. The reactionsolution was concentrated under reduced pressure, and the resultingsolid was washed with DCM to obtain the title compound as a yellow solid(12.6 mg, 67.1%).

LCMS: m/z 434 [M+H]⁺

Using the combination of Compound T18-1 and corresponding boronic acidor the combination of(S)-8-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-benzo[b]carbazol-11(6H)-one and corresponding bromide, the reaction was carried out in thesame manner as Compound GT9-2 to obtain the compounds of the followingTable 27.

TABLE 27 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z 1017 GT9-3

8-((R)-2,3- Dihydroxy-propoxy)- 6,6-dimethyl-3- thiophen-2-yl-5,6-dihydro- benzo[b]carbazol- 11-one B 4.59 434.0 1018 GT9-4

8-((R)-2,3- Dihydroxy-propoxy)- 6,6-dimethyl-3- (1H-pyrazol-4-yl)-5,6-dihydro- benzo[b]carbazol- 11-one B 4.04 418.0 1019 GT9-5

8-((R)-2,3- Dihydroxy-propoxy)- 6,6-dimethyl-3- (2H-pyrazol-3-yl)-5,6-dihydro-benzo[b] carbazol-11-one A 1.51 418.0 1020 GT9-6

8-((R)-2,3- Dihydroxy-propoxy)- 6,6-dimethyl-3- thiazol-5-yl-5,6-dihydro- benzo[b] carbazol-11-one F 1.97 435.0 1021 GT9-7

8-((R)-2,3- Dihydroxy-propoxy)- 3-(3H-imidazol- 4-yl)-6,6- dimethyl-5,6-dihydro-benzo[b] carbazol-11-one H 2.91 418.0

Example 1022 Compound GT10-18-((2R,3R)-2,3,4-Trihydroxybutoxy)-2′,3′,5′,6′-tetrahydrospiro[benzo[b]carbazole-6,4′-pyran]-11(5H)-one

Preparation was carried out in the same manner as Compound N6-1-2.

LCMS: m/z 434 [M+H]⁺

HPLC retention time: 1.56 min (analysis condition A)

The compounds described in the following Table 28—were synthesizedaccording to the method shown below. Specifically, by using the methodfor the preparation of Compound Z10, Z11, Z12 and Z13,8-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one wasprepared from Compound A2 and bromophenol. To the resulting compound, aside chain or a synthetic equivalent thereof was introduced according toMitsunobu reaction that is used for the preparation of Compound A7-1 orthe method that is used for A7-17, etc. After that, if necessary,functional group modification such as deprotection, etc. was carried outto prepare the compounds listed below.

TABLE 28 Exam- HPLC Reten- ple Comp. Condi- tion No. No. StructureCompound Name tion Time m/z 1023 GT11-1

(R)-5-(6,6-Dimethyl- 11-oxo-6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)-4-hydroxy- pentanoic acid H 5.37 395.0 1024 GT11-2

(R)-5-(6,6-Dimethyl- 11-oxo-6,11-dihydro- benzo[b]naphtho[2,3-d] furan-8-yloxymethyl)- pyrrolidin-2-one H 5.50 376.0 1025 GT11-3

8-(3-Hydroxy-propoxy)- 6,6-dimethyl- 6H-benzo[b]naphtho[2,3-d]furan-11-one H 5.97 337.0 1026 GT11-4

8-(3-Ethyl-3-hydroxy- pentyloxy)-6,6- dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-one H 9.29 393.0 1027 GT11-5

(6,6-Dimethyl-11-oxo- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)- acetic acid H 5.65 336.0 1028 GT11-6

4-(6,6-Dimethyl-11-oxo- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)- butyric acid H 6.15 365.0 1029 GT11-7

5-(6,6-Dimethyl-11- oxo-6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)- pentanoic acid H 6.44 379.0 1030 GT11-8

6-(6,6-Dimethyl-11- oxo-6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)- hexanoic acid H 6.77 393.0 1031 GT11-9

2-(6,6-Dimethyl-11- oxo-6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)- N,N-diethyl-acetamide H 6.39 392.0 1032 GT11-10

6,6-Dimethyl-8- (2-morpholin-4-yl- ethoxy)-6H-benzo[b] naphtho[2,3-d]furan-11-one H 4.45 392.0 1033 GT11-11

8-(2-Dimethylamino- ethoxy)-6,6- dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-one H 4.59 350.0

TABLE 29 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1034 GT11- 12

8-((S)-2,3-Dihydroxy- propoxy)-6,6- dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one F 2.40 353.0 1035 GT11- 13

8-((R)-2,3-Dihydroxy- propoxy)-6,6- dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one H 5.07 353.0 1036 GT11- 14

6,6-Dimethyl-8- (2-pyrrolidin-1-yl-ethoxy)- 6H-benzo[b]naphtho[2,3-d]furan-11-one C 3.03 375.9 1037 GT11- 15

6,6-Dimethyl-8- (2-piperidin-1-yl-ethoxy)- 6H-benzo[b]naphtho[2,3-d]furan-11-one C 3.15 389.9 1038 GT11- 16

8-(3-Dimethylamino- propoxy)-6,6-dimethyl- 6H-benzo[b]naphtho[2,3-d]furan-11-one C 3.30 364.2 1039 GT11- 17

8-(2-Azepan-1-yl-ethoxy)- 6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one F 2.35 404.3 1040 GT11- 18

(6,6-Dimethyl-11-oxo- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)- acetic acid methyl ester D 2.38 351.0 1041 GT11- 19

2-(6,6-Dimethyl-11-oxo- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)- N-(2-morpholin- 4-yl-ethyl)-acetamide D 2.03450.0 1042 GT11- 20

6,6-Dimethyl-8- (2-piperazin-1-yl-ethoxy)- 6H-benzo[b]naphtho[2,3-d]furan-11-one C 2.81 391.2 1043 GT11- 21

8-[2-(4-Methanesulfonyl- piperazin-1-yl)-ethoxy]- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one F 2.21 469.1 1044 GT11- 22

2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzol[b] naphtho[2,3-d]furan-8-yloxy)- acetamide O 1.95 336.0 1045 GT11- 23

4-[2-(6,6-Dimethyl-11-oxo- 6,11-dihydro- benzo[b]napntho[2,3-d]furan-8-yloxy)-ethyl]- piperazine- 1-carboxylic acid amide F 2.04 434.01046 GT11- 24

N-(2,3-Dihydroxy-propyl)- 2-(6,6-dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho [2,3-d]furan- 8-yloxy)- acetamide D 1.82 410.0

TABLE 30 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1047 GT11- 25

8-[2-(4-Acetyl-piperazin- 1-yl)-ethoxy]-6,6-dimethyl-6H-benzo[b]naphtho[2,3- d]furan-11-one F 2.10 433.1 1048 GT11- 26

4-[2-(6,6-Dimethyl-11-oxo- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)-acetyl]-piperazine- 1-carboxylic acid tert-butyl ester D 2.53505.0 1049 GT11- 27

8-[2-(2-Hydroxy-ethoxy)- ethoxy]-6,6-dimethyl- 6H-benzo[b]naphtho[2,3-d]furan-11-one H 5.62 367.0 1050 GT11- 28

8-{2-[2-(2-Hydroxy-ethoxy)- ethoxy]-ethoxy}-6,6-dimethyl-6H-benzo[b]naphtho [2,3-d]furan-11-one H 5.64 411.0 1051 GT11- 29

8-(2-Imidazol-1-yl-ethoxy)- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one F 2.05 373.1 1052 GT11- 30

2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yloxy)- N-(2-pyridin-4-yl-ethyl) -acetamide D 2.10 441.01053 GT11- 31

N-(2-Dimethylamino- ethyl)-2-(6,6-dimethyl-11- oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan- 8-yloxy)-acetamide D 2.01 407.0 1054 GT11-32

2-(6,6-Dimethyl-11-oxo- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)-N-[2-(2-hydroxy- ethoxy)-ethyl]- acetamide D 1.88 424.0 1055GT11- 33

6,6-Dimethyl-8-[2- (4-methyl-piperazin-1-yl)- ethoxy]-6H-benzo[b]naphtho[2,3-d]furan-11-one F 1.99 405.2 1056 GT11- 34

6,6-Dimethyl-8-((2R,3R)- 2,3,4-trihydroxy-butoxy)-6H-benzo[b]naphtho[2,3-d] furan-11-one F 2.21 383.0 1057 GT11- 35

8-((R)-2-Hydroxy-3- piperidin-1-yl-propoxy)- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one F 2.25 420.0 1058 GT11- 36

6,6-Dimethyl-8-(2-oxo-2- piperazin-1-yl-ethoxy)-6H-benzo[b]naphtho[2,3-d] furan-11-one D 1.92 405.0 1059 GT11- 37

8-{2-[4-(2-Hydroxy-acetyl)- piperazin-1-yl]-ethoxy}- 6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one F 2.06 449.1 1060 GT11- 38

8-((S)-2-Hydroxy-3- piperidin-1-yl- propoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one F 2.24 420.0

TABLE 31 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1061 GT11- 39

8-[2-((R)-2,3-Dihydroxy- propylamino)-ethoxy]- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one H 4.18 396.0 1062 GT11- 40

8-((S)-4,5-Dihydroxy- pentyloxy)-6,6-dinethyl- 6H-benzo[b]naphtho[2,3-d]furan-11-one F 2.56 381.0 1063 GT11- 41

4-[2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yloxy)- ethyl]-piperazin-2-one F 2.06 405.0 1064GT11- 42

2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yloxy)- N-piperidin-4-yl-acetamide D 1.92 419.0 1065GT11- 43

N-{2-[Bis-(2-hydroxy-ethyl)- amino]-ethyl}-2-(6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b] naphtho[2,3-d]furan- 8-yloxy)-acetamide D1.83 467.0 1066 GT11- 44

N-(3-Dimethylamino-propyl)- 2-(6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho [2,3-d]furan-8-yloxy)- acetamide D 2.08422.0 1067 GT11- 45

N-(2-Diethylamino-ethyl)- 2-(6,6-dimethyl-11- oxo-6,11-dihydro-benzo[b]naphtho[2,3-d] furan-8-yloxy)- acetamide D 2.10 436.0 1068 GT11-46

6,6-Dimethyl-8- (pyrimidin-2-yloxy)- 6H-benzo[b]naphtho[2,3-d]furan-11-one H 6.35 357.0 1069 GT11- 47

8-(2-Ethylamino-ethoxy)- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11- one F 2.15 350.0 1070 GT11- 48

1-[2-(6,6-Dimethyl-11- oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yloxy)- ethyl]-piperazin-2-one H 4.42 405.0 1071GT11- 49

4-[2-(6,6-Dimethyl-11- oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yloxy)- ethyl]-1-methyl-piperazin-2-one H 4.33419.0 1072 GT11- 50

2-(6,6-Dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yloxy)-N- (2-piperazin-1-yl-ethyl)-acetamide A 3.99 448.01073 GT11- 51

2-Dimethylamino-N- [2-(6,6-dimethyl-11-oxo- 6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yloxy)- ethyl]-acetamide D 2.13 408.0 1074 GT11-52

4-[2-(6,6-Dimethyl-11- oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yloxy)- ethyl]-1,1-dimethyl-3-oxo-piperazin-1-ium; chloride H 4.47 433.0

TABLE 32 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1075 GT11- 53

8-{2-[4-(2-Hydroxy-ethyl)- piperazin-1-yl]-ethoxy}- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one A 1.75 435.0 1076 GT11- 54

1-[2-(6,6-Dimethyl-11- oxo-6,11-dihydro- benzo[b]naphtho[2,3-d]furan-8-yloxy)-ethyl]-4- methyl-piperazin-2-one B 4.09 419.0 1077 GT11-55

6,6-Dimethyl-8- (3-piperazin-1-yl-propoxy)- 6H-benzol]naphtho[2,3-d]furan-11-one A 1.75 405.0 1078 GT11- 56

8-{2-[4-((S)-2,3-Dihydroxy- propyl)-piperazin-1-yl]-ethoxy}-6.6-dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-one A 1.72 465.0 1079GT11- 57

8-[2-(2-Hydroxy-1,1- dimethyl-ethylamino)-ethoxy]-6,6-dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-one C 2.57 394.0 1080GT11- 58

8-{2-[Bis-(2-hydroxy-ethyl)- amino]-ethoxy}-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one C 2.77 410.0 1081 GT11- 59

8-[2-(3-Hydroxy-piperidin-1-yl)- ethoxy]-6,6-dimethyl-6H-benzo[d]naphtho[2,3-d] furan-11-one C 2.88 406.0 1082 GT11- 60

8-[2-(2-Hydroxymethyl- pyrrolidin-1-yl)-ethoxy]-6,6-dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-one C 2.82 406.0 1083GT11- 61

8-{2-[Ethyl-(2-hydroxy-ethyl)- amino]-ethoxy}-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one C 2.85 394.0 1084 GT11- 62

6,6-Dimethyl-8-(3-methyl- oxetan-3-ylmethoxy)- 6H-benzo[b]naphtho[2,3-d]furan-11-one C 3.03 363.0 1085 GT11- 63

8-[2-(1-Hydroxymethyl- cyclopentylamino)- ethoxy]-6,6-dimethyl-6H-benzo[b]naphtho [2,3-d]furan-11-one C 2.72 420.0 1086 GT11- 64

8-(4-Hydroxy-pyrrolidin- 2-ylmethoxy)-6,6-dimethyl- 6H-benzo[d]naphtho[2,3-d]furan-11-one Y 2.96 378.0 1087 GT11- 65

6,6-Dimethyl- 8-(piperidin-3-yloxy)- 6H-benzo[b]naphtho[2,3-d]furan-11-one Y 3.03 362.0

The compounds described in the following Table 33 were synthesizedaccording to the method shown below. From Compound A2 and 2-bromophenolhaving a fluorine atom at corresponding position,8-methoxy-6H-benzo[b]naphtho[2,3-d]furan-11-one having a fluorine atomat corresponding position (Compound GT12-1, GT12-2, GT12-5 and GT12-7)was prepared according to the method used for the preparation ofCompound Z10, Z11 and Z12. Further, demethylation was carried outaccording to the method used for the preparation of Compound A6 toobtain 8-hydroxy-6H-benzo[b]naphtho[2,3-d]furan-11-one which has afluorine atom at corresponding position. Thereafter, according toMitsunobu reaction used for the preparation of Compound A7-1 or thealkylation method used for the preparation of Compound A7-17, acorresponding side chain was introduced and, if necessary, functionalgroup modification such as deprotection, etc. was carried out to preparethe compounds listed below.

TABLE 33 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1088 GT12-1

3-Fluoro-8-methoxy- 6,6-dimethyl-6H- benzo[b]naphtho[2,3-d] furan-11-oneA 3.02 311.0 1089 GT12-2

4-Fluoro-8-methoxy- 6,6-dimethyl-6H- benzo[b]naphtho[2,3-d] furan-11-oneA 3.00 311.0 1090 GT12-3

8-(2-Diethylamino-ethoxy)- 3-fluoro-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one B 4.48 396.0 1091 GT12-4

3-Fluoro-6,6-dimethyl- 8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6H-benzo[b]naphtho [2,3-d]furan-11-one H 4.91 401.4 1092 GT12-5

2-Fluoro-8-methoxy- 6,6-dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-oneC 3.01 311.0 1093 GT12-6

8-(2-Diethylamino-ethoxy)- 2-fluoro-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one C 2.09 395.0 1094 GT12-7

1-Fluoro-8-methoxy- 6,6-dimethyl-6H-benzo[b] naphtho[2,3-d]furan-11-oneB 6.26 311.0 1095 GT12-8

8-((R)-2,3-Dihydroxy-propoxy)- 2-fluoro-6,6-dimethyl- 6H-benzo[b]naphtho[2,3-d]furan-11-one C 2.22 371.0 1096 GT12-9

8-(2-Diethylamino-ethoxy)- 1-fluoro-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one B 4.20 396.0 1097 GT12-10

8-((R)-2,3-Dihydroxy-propoxy)- 3-fluoro-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one B 4.82 371.0 1098 GT12-11

8-((R)-2,3-Dihydroxy-propoxy)- 4-fluoro-6,6-dimethyl-6H-benzo[d]naphtho[2,3-d] furan-11-one D 1.80 371.0 1099 GT12-12

8-((R)-2,3-Dihydroxy-propoxy)- 1-fluoro-6,6-dimethyl-6H-benzo[d]naphtho[2,3-d] furan-11-one D 1.85 371.0

The compounds described in the following Table 34 were synthesizedaccording to the method shown below.8-Hydroxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was transformed intotrifluoromethanesulfonic acid ester according to the method used for thepreparation of Compound B1. Subsequently, by carrying out the methodused for the preparation of Compound B2-1 or Compound B2-18, CompoundGT13-1, Compound GT13-2 and Compound GT13-3 were prepared. CompoundGT13-3 was oxidized according to the method used for the preparation ofCompound B3-8 to prepare Compound 13-4.

TABLE 34 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 1100 GT13-1

6,6-Dimethyl-8- morpholin-4-yl-6H- benzo[b]naphtho [2,3-d]furan-11-one F3.04 348.2 B1, B2-1 1101 GT13-2

6,6-Dimethyl-8- (4-methyl-piperazin-1- yl)-6H-benzo[b]naphtho[2,3-d]furan-11-one F 2.13 361.3 B1, B2-1 1102 GT13-3

8-(2-Diisopropylamino- ethylsulfanyl)-6,6- dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one C 3.45 422.0 B1, B2-18 1103 GT13-4

8-(2-Diisopropylamino- ethanesulfonyl)- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one C 3.23 454.0 B3-8

The compounds described in the following Table 35 were synthesizedaccording to the method shown below. Specifically, a side chain wasintroduced to Compound Z13 to prepare Compound GT13-5 according to themethod that is used for the preparation of Compound A7-17. FurtherCompound GT13-5 or trifluoromethanesulfonic acid ester of Compound Z14was hydrolyzed to prepare Compound GT13-6 and Compound GT13-7 accordingto the method used for the preparation of Compound T20.

TABLE 35 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 1104 GT13-5

Trifluoro-methanesulfonic acid 8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro- benzo[b]naphtho[2,3-d] furan-3-yl ester H5.37 526.0 A7-17 1105 GT13-6

8-(2-Diethylamino-ethoxy)- 3-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one B 3.40 394.0 T20 1106 GT13-7

3-Hydroxy-6,6-dimethyl-8- ((2R,3R)-2,3,4-trihydroxy-butoxy)-6H-benzo[b]naphtho [2,3-d]furan-11-one F 1.87 399.0 T20

The compounds described in the following Table 36 were prepared bysubjecting Compound GT13-6 or GT13-7 to Mitsunobu reaction that is usedfor the preparation of Compound A7-1 to introduce a corresponding sidechain or a synthetic equivalent. After that, by carrying outdeprotection, if necessary, the compounds listed below were prepared.

TABLE 36 Exam- Comp. HPLC Retention Me- ple No. No. Structure CompoundName Condition Time m/z thod 1107 GT13- 8

8-(2-Diethylamino- ethoxy)-3-methoxy- 6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one H 4.72 408.0 A7-1 1108 GT13- 9

3-Methoxy-6,6- dimethyl-8-((2R,3R)- 2,3,4-trihydroxy-butoxy)-6H-benzo[b] naphtho[2,3-d] furan-11-one B 4.23 413.2 A7-1 1109GT13- 10

8-(2-Diethylamino- ethoxy)-3-ethoxy- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one H 5.10 422.0 A7-1 1110 GT13- 11

8-(2-Diethylamino- ethoxy)-6,6-dimethyl- 3-propoxy- 6H-benzo[b]naphtho[2,3-d]furan-11-one H 5.63 436.0 A7-1 1111 GT13- 12

3-(2-Hydroxy-ethoxy)- 6,6-dimethyl-8- ((2R,3R)-2,3,4-trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 1.83 443.0A7-1 1112 GT13- 13

3-(3-Hydroxy-propoxy)- 6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 1.94457.0 A7-1 1113 GT13- 14

3-(4-Hydroxy-butoxy)- 6,6-dimethyl-8- ((2R,3R)-2,3,4-trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 2.01 471.0A7-1 1114 GT13- 15

3-Isopropoxy- 6,6-dimethyl-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6H-benzo[b]naphtho [2,3-d]furan-11-one H 5.40 441.0 A7-1 1115 GT13- 16

3-(2-Methoxy-ethoxy)- 6,6-dimethyl-8- ((2R,3R)-2,3,4-trihydroxy-butoxy)- 6H-benzo[b] naphtho[2,3-d] furan-11-one F 2.17 457.0A7-1 1116 GT13- 17

3-(3-Methoxy-propoxy)- 6,6-dimethyl-8- ((2R,3R)-2,3,4-trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 2.34 471.0A7-1 1117 GT13- 18

3-(4-Methoxy-butoxy)- 6,6-dimethyl-8- ((2R,3R)-2,3,4-trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 2.45 485.0A7-1 1118 GT13- 19

3-((S)-2,3-Dihydroxy- propoxy)-6,6-dimethyl- 8-((2R,3R)-2,3,4-trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 1.69 473.0A7-1- A7-14- 1 1119 GT13- 20

3-((R)-2,3-Dihydroxy- propoxy)-6,6-dimethyl- 8-((2R,3R)-2,3,4-trihydroxy-butoxy)- 6H-benzo[b]naphtho [2,3-d]furan-11-one F 1.69 473.0A7-1- A7-14- 1

The compounds described in the following Table 37 were prepared fromCompound GT13-7 according to carbamation that is used for thepreparation of Compound A9-1.

TABLE 37 Exam- Reten- ple Comp. HPLC tion Me- No. No. Structure CompoundName Condition Time m/z thod 1120 GT13- 21

(4-Methoxy-phenyl)- carbamic acid 6,6- dimethyl-11-oxo-8-((2R,3R)-2,3,4- trihydroxy-butoxy)- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-3-yl ester B 4.34 548.2 A9-1 1121 GT13- 22

(3-Methoxy-phenyl)- carbamic acid 6,6- dimethyl-11-oxo-8-((2R,3R)-2,3,4- trihydroxy-butoxy)- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-3-yl ester B 4.69 548.2 A9-1 1122 GT13- 23

(2-Methoxy-phenyl)- carbamic acid 6,6- dimethyl-11-oxo-8-((2R,3R)-2,3,4- trihydroxy-butoxy)- 6,11-dihydro- benzo[b]naphtho[2,3-d]furan-3-yl ester B 4.99 548.3 A9-1 1123 GT13- 24

Phenyl-carbamic acid 6,6-dimethyl-11- oxo-8-((2R,3R)-2,3,4- trihydroxy-butoxy)-6,11-dihydro- benzo[b]naphtho [2,3-d]furan-3-yl ester B 4.67518.2 A9-1 1124 GT13- 25

Cyclohexyl- carbamic acid 6,6-dimethyl-11- oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)- 6,11-dihydro- benzo[b]naphtho [2,3-d]furan-3-ylester B 4.94 524.2 A9-1 1125 GT13- 26

Benzyl-carbamic acid 6,6-dimethyl-H-oxo-8- ((2R,3R)-2,3,4-trihydroxy-butoxy)- 6,11-dihydro- benzo[b]naphtho [2,3-d]furan-3-ylester A 2.09 532.3 A9-1 1126 GT13- 27

Methyl-phenyl- carbamic acid 6,6- dimethyl-11-oxo-8- ((2R,3R)-2,3,4-trihydroxy-butoxy)- 6,11-dihydro- benzo[b]naphtho [2,3-d]furan-3-ylester B 4.88 532.3 A9-1

The compounds described in the following Table 38 were prepared fromcorresponding intermediates by alkylation and carbamation based on themethod described in the Table.

TABLE 38 Exam- Reten- ple Comp. HPLC tion Me- No. No. Structure CompoundName Condition Time m/z thod 1127 GT13- 28

3-(2-Diethylamino- ethoxy)-8-methoxy- 6,6-dimethyl-6H- benzo[b]naphtho[2,3-d] furan-11-one H 4.65 408.0 A7-17 1128 GT13- 29

2-[8-((R)-2,3- Dihydroxy- propoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro-benzo[b] naphtho[2,3-d] furan-3-yloxy]- N-phenyl-acetamide B 4.70 502.0A7-17 A8-1 T13-3 1129 GT13- 30

(4-tert- Butyl-phenyl)- carbamic acid 8- ((R)-2,3-dihydroxy-propoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro- benzo[b] naphtho[2,3-d]furan-3-yl ester B 6.19 544.3 A9-1 1130 GT13- 31

(2-tert- Butyl-phenyl)- carbamic acid 8- ((R)-2,3-dihydroxy- propoxy)-6,6-dimethyl- 11-oxo-6,11- dihydro-benzo[b] naphtho[2,3-d] furan-3-ylester B 5.74 544.3 A9-1 1131 GT13- 32

(5-tert-Butyl-2- methoxy-phenyl)- carbamic acid 8- ((R)-2,3-dihydroxy-propoxy)-6,6- dimethyl-11-oxo- 6,11-dihydro- benzo[b] naphtho[2,3-d]furan-3-yl ester B 6.52 574.3 A9-1 1132 GT13- 33

6,6-Dimethyl-3- (pyrimidin- 2-yloxy)-8- ((2R,3R)-2,3,4- trihydroxy-butoxy)-6H- benzo[b] naphtho[2,3-d] furan-11-one H 4.14 477.0 A7-17

Example 1133 Compound GT14-13-Chloro-8-((R)-2,3-dihydroxy-propoxy)-6,6-dimethyl-5,6-dihydro-benzo[f]pyrido[4,3-b]indol-11-one

Compound BZ2-2 was demethylated according to the method used for thepreparation of Compound A6, and subsequently introduced with asubstituent group and deprotected according to the method used for thepreparation of Compound A7-14-1 and A7-14-2.

LCMS: m/z 386 [M+H]⁺

HPLC retention time: 3.02 min (analysis condition B)

Example 1134 Compound GT15-1 2-Iodo-3-(4-methoxy-benzyloxy)-pyridine

2-Iodo-pyridin-3-ol (50 mg, 0.226 mmol), K₂CO₃ (62 mg, 0.452 mmol) andDMF (2 ml) were added with para-methoxybenzyl chloride (46 μL, 0.339mmol), and the mixture was stirred overnight at 45° C. The resultant wasadded with water, and then extracted with ethyl acetate. The organiclayer was washed with saturated brine, and the resulting residuesobtained after concentration under reduced pressure were purified bysilica gel column (ethyl acetate/hexane) to obtain the title compound(21 mg, 27%).

LCMS: m/z 342 [M+H]⁺

HPLC retention time: 3.44 min (analysis condition Y)

Example 1135 Compound GT15-27-Methoxy-3-[3-(4-methoxy-benzyloxy)-pyridin-2-yl]-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

Toluene (0.5 ml) was added to7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 36mg), 2-iodo-3-(4-methoxy-benzyloxy)-pyridine (Compound GT15-1, 50 mg),sodium t-butoxide (35.3 mg), Pd₂dba₃ (13.5 mg) and Xantphos (17 mg), andthe mixture was stirred and heated at 80° C. for 2.5 hrs under nitrogenatmosphere. After cooling, the reaction mixture was diluted with ethylacetate and subjected to Celite filtration. The organic layer was washedwith saturated aqueous solution of sodium bicarbonate and saturatedbrine, and then concentrated under reduced pressure. The resultingresidues were purified by silica gel column (ethyl acetate/hexane) toobtain the title compound (27 mg, 44%).

LCMS: m/z 419 [M+H]⁺

HPLC retention time: 3.31 min (analysis condition Y)

Example 1136 Compound GT15-38-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-4-aza-benzo[b]fluorene

To the mixture of7-methoxy-3-[3-(4-methoxy-benzyloxy)-pyridin-2-yl]-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(Compound GT15-2, 21 mg) and ethyl acetate (0.8 ml), sulfuric acid (0.2ml) was added. The mixture was stirred and heated at 70° C. for 5 hrs.After cooling, the reaction mixture was neutralized with 2 N aqueoussolution of sodium hydroxide. The mixture was diluted with ethylacetate. The organic layer was washed with saturated aqueous solution ofsodium bicarbonate and saturated brine, and then concentrated underreduced pressure. The resulting residues were purified by silica gelcolumn (ethyl acetate/hexane) to obtain the title compound (7 mg, 50%).

LCMS: m/z 280 [M+H]⁺

HPLC retention time: 2.71 min (analysis condition Y)

Example 1137 Compound GT15-48-Methoxy-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one

8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-4-aza-benzo[b]fluorene(Compound GT15-3, 22 mg) was dissolved in MeCN (0.26 ml) and water (0.13ml), added with sodium chlorite (14 mg) and N-hydroxyphthalimide (2.6mg), and the mixture was stirred at 40° C. for 1 hr. The reactionmixture was diluted with ethyl acetate. The organic layer was washedwith saturated aqueous solution of sodium bicarbonate and saturatedbrine, and then concentrated under reduced pressure. The resultingresidues were purified by silica gel column (ethyl acetate/hexane) toobtain the title compound (16 mg, 70%).

LCMS: m/z 294 [M+H]⁺

HPLC retention time: 2.85 min (analysis condition Y)

Example 1138 Compound GT15-58-Hydroxy-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one

Mixture of8-methoxy-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one(Compound GT15-4, 25 mg) and pyridine hydrochloric acid salt (492 mg)was stirred and heated at 178° C. overnight. The reaction mixture wascooled, and added with water. The mixture was neutralized with saturatedaqueous solution of sodium bicarbonate and extracted with DCM. Theorganic layer was washed with saturated brine, and then concentratedunder reduced pressure. The resulting residues were purified by silicagel column (DCM/MeOH) to obtain the title compound (13 mg, 54%).

LCMS: m/z 280 [M+H]⁺

HPLC retention time: 2.30 min (analysis condition Y)

Example 1139 Compound GT15-68-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one

In the same manner as Compound A7-1, the title compound was synthesizedfrom Compound GT15-5 and Compound T22-0 (29 mg, 50%).

LCMS: m/z 538 [M+H]⁺

HPLC retention time: 3.64 min (analysis condition Y)

Example 1140 Compound GT15-710,10-Dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-10H-11-oxa-4-aza-benzo[b]fluoren-5-one

To the mixture of8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b]fluoren-5-one (CompoundGT15-6, 27 mg), MeOH (0.1 ml) and THF (0.3 ml), 0.5 N sulfuric acid (0.1ml) was added, and the mixture was stirred and heated at 55 to 60° C.for 4 hrs. The reaction mixture was neutralized with saturated aqueoussolution of sodium bicarbonate. The resulting solid was filtered andwashed with diethyl ether. The filtrate was extracted with the mixturesolution of DCM and MeOH (DCM:MeOH=10:1). The organic layer was washedwith saturated brine, and dried over magnesium sulfate. The filteredsolid and the residues obtained after concentration under reducedpressure were combined and purified by silica gel column (DCM/MeOH) toobtain the title compound (5.4 mg, 28%).

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 2.02 min (analysis condition Y)

Example 1141 Compound GT15-87-Methoxy-3-(3-methoxymethoxy-pyridin-4-yl)-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,924 mg), 4-iodo-3-methoxymethoxy-pyridine (1 g), sodium t-butoxide (906mg), Pd₂dba₃ (173 mg) and S-Phos (185 mg), toluene (19 ml) was added,and the mixture was stirred and heated at 70° C. for 2 hrs undernitrogen atmosphere. The reaction mixture was diluted with ethyl acetateand filtered through Celite. The organic layer was washed with saturatedaqueous solution of sodium bicarbonate and saturated brine, and thenconcentrated under reduced pressure. The resulting residues werepurified by silica gel column (ethyl acetate/hexane) to obtain the titlecompound (610 mg, 47%).

LCMS: m/z 342 [M+H]⁺

HPLC retention time: 2.60 min (analysis condition Y)

Example 1142 Compound GT15-93-(3-Hydroxy-pyridin-4-yl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

Mixture of7-methoxy-3-(3-methoxymethoxy-pyridin-4-yl)-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(Compound GT15-8, 430 mg) and 4 N hydrochloric acid dioxane solution (5ml) was heated and stirred at room temperature for 1.5 hrs. The reactionmixture was neutralized with 2 N aqueous solution of sodium hydroxide.The resulting mixture was extracted with the mixture of DCM and MeOH(DCM:MeOH=9:1). The residues obtained after concentration under reducedpressure were purified by silica gel column (DCM/MeOH) to obtain thetitle compound (280 mg, 75%).

LCMS: m/z 298 [M+H]⁺

HPLC retention time: 2.41 min (analysis condition Y)

Example 1143 Compound GT15-108-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-2-aza-benzo[b]fluorene

Mixture of3-(3-hydroxy-pyridin-4-yl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one(Compound GT15-9, 270 mg) and methanesulfonic acid (1 ml) was stirredand heated at 110° C. for 0.5 hrs. After cooling, the reaction mixturewas neutralized with 2 N aqueous solution of sodium hydroxide. Theresulting mixture was extracted with the mixture of DCM and MeOH(DCM:MeOH=9:1). The organic layer was concentrated under reducedpressure, and the resulting residues were purified by silica gel column(DCM/MeOH) to obtain the title compound (110 mg, 43%).

LCMS: m/z 280 [M+H]⁺

HPLC retention time: 2.53 min (analysis condition Y)

Example 1144 Compound GT15-118-Methoxy-10,10-dimethyl-10OH-11-oxa-2-aza-benzo[b]fluoren-5-one

8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-2-aza-benzo[b]fluorene(Compound GT15-10, 20 mg) was dissolved in acetonitrile (0.2 ml) andwater (0.15 ml), added with sodium chlorite (16 mg) andN-hydroxyphthalimide (2.3 mg), and the mixture was stirred at 40° C. for40 min. To the reaction mixture, ethyl acetate was added. The organiclayer was washed with saturated aqueous solution of sodium bicarbonateand saturated brine, and then concentrated under reduced pressure. Theresulting residues were purified by silica gel column (ethylacetate/hexane) to obtain the title compound (12 mg, 57%).

LCMS: m/z 294 [M+H]⁺

HPLC retention time: 2.51 min (analysis condition Y)

Example 1145 Compound GT15-128-Hydroxy-10,10-dimethyl-10H-11-oxa-2-aza-benzo[b]fluoren-5-one

DCM (0.34 ml) solution of8-methoxy-10,10-dimethyl-10H-11-oxa-2-aza-benzo[b]fluoren-5-one(Compound GT15-11, 10 mg) was cooled to −78° C., added with the DCMsolution (0.17 ml) of 1.0 M BBr₃, and the mixture was stirred at roomtemperature overnight. To the reaction mixture, water and saturatedaqueous solution of sodium bicarbonate were added, and the solidproduced therefrom was filtered off. The filtrate was extracted with themixture solution of DCM and MeOH (DCM:MeOH=9:1). The organic layer waswashed with saturated brine. The filtered solid and the residuesobtained after concentration under reduced pressure were combined toobtain the title compound (9.5 mg, 99%).

LCMS: m/z 280 [M+H]⁺

HPLC retention time: 2.50 min (analysis condition Y)

Example 1146 Compound GT15-138-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-10,10-dimethyl-10H-11-oxa-2-aza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound GT15-12 and Compound T22-0(38 mg, 66%).

LCMS: m/z 538 [M+H]⁺

HPLC retention time: 3.55 min (analysis condition Y)

Example 1147 Compound GT15-1410,10-Dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-10H-11-oxa-2-aza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing CompoundGT15-7, the title compound was prepared from Compound GT15-13 (2.1 mg,84%).

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 1.70 min (analysis condition Y)

Example 1148 Compound GT15-15 3-Bromo-2-(4-methoxy-benzyloxy)-pyridine

Under the same conditions as the method for synthesizing Compound G15-1,the title compound was prepared from 3-bromo-pyridin-2-ol (740 mg, 88%).

LCMS: m/z 295 [M+H]⁺

HPLC retention time: 2.86 min (analysis condition Y)

Example 1149 Compound GT15-167-Methoxy-3-[2-(4-methoxy-benzyloxy)-pyridin-3-yl]-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,845 mg), 3-bromo-2-(4-methoxy-benzyloxy)-pyridine (Compound GT15-15,1.46 g), sodium t-butoxide (597 mg), palladium acetate (18.6 mg) andtri-tert-butylphosphine tetrafluoroboric acid (21 mg), toluene (10 ml)and THF (2 ml) were added and the mixture was stirred and heated at 90°C. for 2.5 hrs under nitrogen atmosphere. After cooling, the reactionmixture was added with saturated aqueous solution of ammonium chloride,and then extracted with ethyl acetate. The organic layer was washed withsaturated brine, and the residues obtained after concentration underreduced pressure were purified by silica gel column (ethylacetate/hexane) to obtain the title compound (140 mg, 8%).

LCMS: m/z 419 [M+H]⁺

HPLC retention time: 3.50 min (analysis condition Y)

Example 1150 Compound GT15-178-Methoxy-10,10-dimethyl-10H-11-oxa-1-aza-benzo[b] fluoren-5-one

Under the same conditions as the method for synthesizing CompoundGT15-3, the title compound was prepared from Compound GT15-16 (49 mg,52%).

LCMS: m/z 294 [M+H]⁺

HPLC retention time: 3.39 min (analysis condition Y)

Example 1151 Compound GT15-18 8-Hydroxy-10,10-dimethyl-10OH-11-oxa-1-aza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing CompoundGT15-5, the title compound was prepared from Compound GT15-17 (6.5 mg,51%).

LCMS: m/z 280 [M+H]⁺

HPLC retention time: 3.10 min (analysis condition Y)

Example 1152 Compound GT15-198-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-10,10-dimethyl-10H-11-oxa-1-aza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound GT15-18 and Compound T22-0(4.5 mg, 11%).

LCMS: m/z 538 [M+H]⁺

HPLC retention time: 3.88 min (analysis condition Y)

Example 1153 Compound GT15-2010,10-Dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-10H-11-oxa-1-aza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing CompoundGT15-7, the title compound was prepared from Compound GT15-19 (7.9 mg,51%).

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 2.57 min (analysis condition Y)

Example 1154 Compound GT15-218-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-3-aza-benzo[b]fluorene

To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2,2.5 g), 3-bromo-4-chloro-pyridine (2 g), sodium t-butoxide (3 g),Pd₂dba₃ (476 mg), and S-Phos (512 mg), toluene (20 ml) was added, andthe mixture was stirred and heated at 100° C. overnight under nitrogenatmosphere. After cooling, the reaction mixture was diluted with ethylacetate and filtered through Celite. The organic layer was washed withsaturated aqueous solution of sodium bicarbonate and saturated brine.Thereafter, the organic layer was dried over sodium sulfate. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column (ethyl acetate/hexane) to obtain the titlecompound (112 mg, 4%).

LCMS: m/z 280 [M+H]⁺

HPLC retention time: 2.46 min (analysis condition Y)

Example 1155 Compound GT15-228-Methoxy-10,10-dimethyl-10H-11-oxa-3-aza-benzo[b] fluoren-5-one

Under the same conditions as the method for synthesizing CompoundGT15-3, the title compound was prepared from Compound GT15-21 (49 mg,52%).

LCMS: m/z 294 [M+H]⁺

HPLC retention time: 2.30 min (analysis condition Y)

Example 1156 Compound GT15-238-Hydroxy-10,10-dimethyl-10H-11-oxa-3-aza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing CompoundGT15-12, the title compound was prepared from Compound GT15-22 (110 mg,77%).

LCMS: m/z 280 [M+H]⁺

HPLC retention time: 1.95 min (analysis condition Y)

Example 1157 Compound GT15-248-[(4R,5R)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-10,10-dimethyl-10H-11-oxa-3-aza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound A7-1,the title compound was prepared from Compound GT15-23 and Compound T22-0(38 mg, 49%).

LCMS: m/z 538 [M+H]⁺

HPLC retention time: 3.40 min (analysis condition Y)

Example 1158 Compound GT15-2510,10-Dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-10H-11-oxa-3-aza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing CompoundGT15-7, the title compound was prepared from Compound GT15-24 (17 mg,72%).

LCMS: m/z 384 [M+H]⁺

HPLC retention time: 1.48 min (analysis condition Y)

Example 1159 Compound GT16-1 2-(2-Bromo-4-methoxy-phenyl)-propan-2-ol

To the mixture of 1-(2-bromo-4-methoxyphenyl)-ethanone (300 mg)dissolved in THF solution (3 ml), MeMgBr (3 M THF solution, 0.52 ml) wasadded at 0° C. under nitrogen atmosphere. Then, the mixture was stirredat room temperature for 6 hrs. The reaction mixture was added withsaturated aqueous solution of ammonium chloride and extracted with ethylacetate. The organic layer was washed with saturated brine, and theresidues obtained after concentration under reduced pressure werepurified by silica gel column (ethyl acetate/hexane) to obtain the titlecompound (220 mg, 69%).

¹H-NMR (CDCL₃) δ: 7.55 (1H, d), 7.14 (1H, d), 6.83 (1H, dd), 3.79 (3H,s), 2.72 (1H, s), 1.73 (6H, s)

Example 1160 Compound GT16-22-[1-(2-Bromo-4-methoxyphenyl)-1-methylethyl]benzofuran

Mixture comprising 2-(2-bromo-4-methoxyphenyl)-propan-2-ol (100 mg),2,3-benzofuran (0.19 ml) and polyphosphoric acid (1 g) was stirred andheated at 90° C. for 30 min. The reaction mixture was added with waterand extracted with DCM. The residues obtained after concentration underreduced pressure were purified by silica gel column (DCM/hexane) toobtain the title compound (143 mg, 51%).

¹H-NMR (CDCL₃) δ: 7.4-7.5 (1H, m), 7.3-7.4 (2H, m), 7.1-7.25 (3H, m),6.87 (1H, dd), 6.42 (1H, s) 3.79 (3H, s), 1.84 (6H, s)

Example 1161 Compound GT16-32-(1-Benzofuran-2-yl-1-methyl-ethyl)-5-methoxy-benzoic Acid

To the mixture comprising2-[1-(2-bromo-4-methoxyphenyl)-1-methylethyl]benzofuran (140 mg) and THF(2 ml), n-butyl lithium (2.5 M solution, 0.17 ml) was added at −78° C.under nitrogen atmosphere. The mixture was stirred for 20 min. Theresulting reaction mixture was flushed with carbon dioxide gas for 15min. Then, the reaction mixture was added with saturated aqueoussolution of ammonium chloride and extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and theresidues obtained after concentration under reduced pressure werepurified by silica gel column (DCM/MeOH) to obtain the title compound(68 mg, 54%).

LCMS: m/z 311 [M+H]⁺

HPLC retention time: 2.92 min (analysis condition Y)

Example 1162 Compound GT16-49-Methoxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one

To the DCM solution (1 ml) of2-(1-benzofuran-2-yl-1-methylethyl)-5-methoxy benzoic acid (63 mg),trifluoroacetic anhydride (0.03 ml) was added at room temperature undernitrogen atmosphere. The mixture was stirred for 30 min. The reactionmixture was then added with water and extracted with DCM. The organiclayer was dried over sodium sulfate. The residues obtained afterconcentration under reduced pressure were purified by silica gel column(DCM) to obtain the title compound (50 mg, 84%).

LCMS: m/z 293 [M+H]⁺

HPLC retention time: 3.49 min (analysis condition Y)

Example 1163 Compound GT16-59-Hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

Under the same conditions as the method for synthesizing Compound A6,the title compound was prepared from Compound GT16-4.

LCMS: m/z 279 [M+H]⁺

HPLC retention time: 3.05 min (analysis condition Y)

Example 1164 Compound GT16-69-(2-Diethylamino-ethoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound GT16-5.

LCMS: m/z 378 [M+H]⁺

HPLC retention time: 2.41 min (analysis condition Y)

Example 1165 Compound GT16-7 9-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

Under the same conditions as the method for synthesizing Compound A7-17,the title compound was prepared from Compound GT16-5 andtoluene-4-sulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-yl methylester.

LCMS: m/z 393 [M+H]⁺

HPLC retention time: 3.22 min (analysis condition Y)

Example 1166 Compound GT16-89-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

Under the same conditions as the method for synthesizing CompoundA7-14-2, the title compound was prepared from Compound GT16-7.

LCMS: m/z 353 [M+H]⁺

HPLC retention time: 2.83 min (analysis condition Y)

Example 1167 Compound GT16-93-(6,6-Dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-9-yl)-benzoicAcid

In the same manner as Compound GT9-2, the title compound was synthesizedfrom Compound GT16-5.

LCMS: m/z 383 [M+H]⁺

HPLC retention time: 7.11 min (analysis condition H)

Example 1168 Compound GT16-109-(4-Hydroxymethyl-phenyl)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

In the same manner as Compound GT9-2, the title compound was synthesizedfrom Compound GT16-5.

LCMS: m/z 369 [M+H]⁺

HPLC retention time: 6.97 min (analysis condition H)

The compounds described in the following Table 39 were synthesizedaccording to the method shown below. Specifically, Compound GT17-1 wasprepared from 8-methoxy-1,1-dimethyl-3,4-dihydro-1H naphthalen-2-one andbromophenol by following the method that is used for the preparation ofCompound Z10, Z11 and Z12. Compound GT17-1 was demethylated according tothe method used for the preparation of Compound A6, and as a result7-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one wasprepared. The resulting hydroxy compound was subjected to the alkylationaccording to the method used for the preparation of A7-1, or Mitsunobureaction used for the preparation of Compound A7-17 for introducing acorresponding side chain or a synthetic equivalent thereof. Thereafter,if necessary, functional group modification was carried out to prepareCompound GT17-2 and Compound GT17-3.

TABLE 39 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1169 GT17-1

7-Methoxy-6,6-dimethyl-6H- benzo[b]naphtho[2,3-d] furan-11-one Y 13.42293.0 1170 GT17-2

7-(2-Diethylamino-ethoxy)-6,6- dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one Y  9.92 378.0 1171 GT17-3

7-((R)-2,3-Dihydroxy-propoxy)- 6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one Y 11.68 353.0

The compounds described in the following Table 40 were synthesizedaccording to the method shown below.

By using the method used for the preparation of Compound Z10, Z11 andZ12, Compound GT18-1 was prepared from Compound M1 and bromophenol.Further, according to the method used for the preparation of CompoundA6, Compound GT18-1 was demethyalted to prepare8-hydroxy-11H-spiro[benzo[b]naphtho[2,3-d]furan-6,1′-cyclopentan]-11-one,which was then introduced with a side chain based on the alkylation thatis used for the preparation of Compound A7-1. As a result, CompoundGT18-2 was prepared.

The following spiro compounds were prepared from7-methoxy-3,4-dihydro-1H-naphthalen-2-one and corresponding dibromide inthe same manner as above.

TABLE 40 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1172 GT18-1

8-methoxy-11H- spiro[benzo[b]naptho [2,3-d]furan-6,1′-cyclopentane]-11-one Y 10.00 319.0 1173 GT18-2

8-(2-diethylamino-ethoxy)- 11H-spiro[benzo[b]naptho [2,3-d]furan-6,1′-cyclopentane]-11-one C  2.19 404.0 1174 GT18-3

8-(2-diethylamino-ethoxy)- 11H-spiro[benzo[b] naptho[2,3-d]furan-6,1′-cyclohexane]-11-one C  3.28 418.2 1175 GT18-4

8-((2R, 3R)-2, 3, 4- trihydroxybutoxy)-11H- spiro[benzo[b]naptho[2,3-d]furan-6,1′- cyclohexane]-11-one A  2.26 423.2 1176 GT18-5

8-methoxy-11H- spiro[benzo[b] naptho[2,3-d]furan-6,1′-cyclobutane]-11-one Y  9.00 305.0 1177 GT18-6

8-(2-diethylamino-ethoxy)- 2′,3′,5′,6′-tetrahydro-11H-spiro[benzo[b]naptho[2,3-d] furan-6,4′-pyran]-11-one B  4.05 420.3

Example 1178 Compound GT19-18-(2-Diethylamino-ethoxy)-6,6-dimethyl-3-phenyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

According to the method described before, the preparation was carriedout by using 7-methoxy-1,1-dimethyl-3,4-dihydro-1H naphthalen-2-one and2-bromo-5-trifluorophenol.

LCMS: m/z 446 [M+H]⁺

HPLC retention time: 3.25 min (analysis condition C)

Example 1179 Compound GT19-28-(2-Diethylamino-ethoxy)-6,6-dimethyl-3-phenyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

By carrying out Suzuki coupling of Compound GT23-5 and a correspondingboronic acid reagent based on the method that is used for thepreparation of Compound GT9-2, the title compound was prepared.

LCMS: m/z 454 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition F)

Example 1180 Compound GT20-18-Hydroxy-6,6-dimethyl-3-(2-phenyl-ethanesulfonyl)-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (72.2mg, 0.203 mmol), 2-phenylethanethiol (0.0297 ml, 0.221 mmol), Pd₂dba₃(9.3 mg, 0.0102 mmol), Xantphos (11.6 mg, 0.020 mmol) and ethyldiisopropylamine (0.068 ml, 0.40 mmol) were dissolved in dioxane (0.6ml), and the mixture was stirred at 110° C. for 16 hrs under nitrogenatmosphere. Water and ethyl acetate were added to the mixture to give asuspension, which was then filtered. The organic layer was washed withwater and saturated brine, and then concentrated under reduced pressure.The resulting residues were purified by silica gel column (ethylacetate/hexane). The resulting residues were dissolved in THF (4 ml),and the supernatant liquid (2 ml) was taken and added with water (1 ml)and OXONE (99 mg). The resulting mixture was stirred at room temperatureovernight. The reaction solution was partitioned between water and ethylacetate. The organic layer was washed with brine, and then concentratedunder reduced pressure. The resulting residues were purified by silicagel column (ethyl acetate/hexane) to obtain the title compound (37.1mg).

LCMS: m/z 446 [M+H]⁺

HPLC retention time: 2.51 min (analysis condition F)

Example 1181 Compound GT20-26,6-Dimethyl-3-(2-phenyl-ethanesulfonyl)-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[b]carbazol-11-oneand Compound GT20-38-Isopropoxy-6,6-dimethyl-3-(2-phenyl-ethanesulfonyl)-5,6-dihydro-benzo[b]carbazol-11-one

8-Hydroxy-6,6-dimethyl-3-(2-phenyl-ethanesulfonyl)-5,6-dihydro-benzo[b]carbazol-11-one(30 mg, 0.0673 mmol),[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]methanol(22.3 mg, 0.0808 mmol), and PPh₃ (23 mg, 0.0875 mmol) were dissolved inTHF (0.5 ml), added with DIAD (0.0169 ml, 0.0808 mmol), and the mixturewas stirred at 50° C. overnight. After cooling, the reaction solutionwas filtered and concentrated under reduced pressure. The resultingresidues were purified by silica gel column (ethyl acetate/hexane). Theresulting residues were dissolved in THF (0.4 ml) and water (0.13 ml),added with camphor sulfonic acid (28.1 mg, 0.121 mmol), and thensubjected to microwave irradiation at 80° C. for 15 min under nitrogenatmosphere. Ethyl acetate was added to the resultant. The organic layerwas washed with saturated aqueous solution of sodium hydrocarbonate andsaturated brine, and then concentrated under reduced pressure. Theresulting residues were purified by thin layer chromatography (MeOH/DCM)to obtain Compound GT20-2 (10.5 mg) and Compound GT20-3 (2.4 mg).

Compound GT20-2

LCMS: m/z 550 [M+H]⁺

HPLC retention time: 2.20 min (analysis condition F)

Compound GT20-3

LCMS: m/z 488 [M+H]⁺

HPLC retention time: 3.13 min (analysis condition F)

Example 1182 Compound GT20-43-Methanesulfonyl-6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-5,6-dihydro-benzo[b]carbazol-11-one

The DMA solution (0.6 ml) comprising Compound GT23-2 (59.6 mg, 0.167mmol), sodium methanethiolate (77 mg, 1.10 mmol), Pd₂dba₃ (23.7 mg,0.0259 mmol) and Xantphos (29.7 mg, 0.0513 mmol) was subjected tomicrowave irradiation at 180° C. for 30 min under nitrogen atmosphere.The reaction solution was partitioned between aqueous solution ofpotassium dihydrophosphoric acid and ethyl acetate. The organic layerwas washed with saturated brine, and then concentrated under reducedpressure. The resulting residues were purified by silica gel column(ethyl acetate/hexane and MeOH/DCM). The resulting solids were dissolvedin THF (1 ml) and water (0.5 ml), and then added with OXONE (101.4 mg).The resulting mixture was stirred at room temperature for 2 hrs. Thereaction solution was partitioned between water and ethyl acetate. Theorganic layer was washed with saturated brine, and then concentratedunder reduced pressure. The resulting residues were suspended and washedwith MTBE. The resulting solid was dissolved in THF (0.4 ml), and addedwith PPh₃ (37 mg, 0.141 mmol),[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol(39.0 mg, 0.141 mmol) and DEAD (2.2 M toluene solution, 0.064 ml, 0.141mmol), and the mixture was stirred at 40° C. for 4 hrs under nitrogenatmosphere. The reaction solution was partitioned between water andethyl acetate. The organic layer was washed with saturated brine, andthen concentrated under reduced pressure. The resulting residues werepurified by silica gel column (MeOH/DCM). Thus-obtained product wasdissolved in THF (0.25 ml) and MeOH (0.05 ml), added with 0.5 M sulfuricacid (0.1 ml), and the mixture was stirred at 60° C. for 5 hrs. Aftercooling, the mixture was added with diethyl ether and sodiumhydrocarbonate (13 mg, 0.15 mmol). The separated aqueous layer wasfiltered, concentrated under reduced pressure, and suspended andpurified with MeOH to obtain the title compound as a white solid (10.4mg, 14%).

LCMS: m/z 460 [M+H]⁺

HPLC retention time: 1.71 min (analysis condition F)

Example 1183 Compound GT20-58-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-3-methylsulfanyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (47.3 mg,0.101 mmol), sodium methanethiolate (34.6 mg, 0.493 mmol), Pd₂(dba)₃(13.1 mg, 0.0413 mmol), and Xantphos (17.9 mg, 0.0309 mmol) weredissolved in DMA (0.5 ml) and subjected to microwave irradiation at 200°C. for 30 min under nitrogen atmosphere. The resultant was partitionedbetween aqueous solution of potassium dihydrophosphoric acid and ethylacetate. The organic layer was washed with saturated brine, and thenconcentrated under reduced pressure. The resulting residues werepurified by thin layer chromatography (ethyl acetate/DCM). The resultingsolid was dissolved in THF (0.23 ml) and MeOH (0.06 ml), and then addedwith 0.5 M sulfuric acid (0.12 ml). The resulting mixture was stirred at60° C. for 2 hrs. The reaction solution was diluted with diethyl etherand neutralized with sodium hydrocarbonate (15.5 mg, 0.185 mmol).Thereafter, the solution was partitioned between brine and ethylacetate. The organic layer was concentrated under reduced pressure. Theresulting residues were added with diethyl ether. The precipitated solidwas filtered to obtain the title compound as a white solid (15.8 mg,39%).

LCMS: m/z 398 [M+H]⁺

HPLC retention time: 4.46 min (analysis condition H)

Example 1184 Compound GT20-58-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-3-thiazol-2-yl-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (47 mg, 0.10mmol), bis (pinacolate)diborone (33 mg, 0.13 mmol), Pd (dppf)₂Cl₂.DCM(8.2 mg, 0.010 mmol) and potassium acetate (294 mg, 0.3 mmol) weredissolved in dioxane (0.6 ml), and the mixture was stirred at 100° C.overnight under nitrogen atmosphere. The resultant was partitionedbetween aqueous solution of potassium dihydrophosphoric acid and ethylacetate. The organic layer was washed with saturated brine, and thenconcentrated under reduced pressure. The resulting residues werepurified by silica gel column (ethyl acetate/DCM) to obtain8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5,6-dihydro-benzo[b]carbazol-11-one(30.2 mg). The product (11 mg) was dissolved in DMA (0.4 ml), added with2-bromothiazole (0.0038 ml, 0.0428 mmol), Pd (PPh₃)₄ (5.3 mg, 0.00459mmol), potassium phosphate (27.4 mg, 0.129 mmol) and water (0.1 ml), andthe mixture was subjected to microwave irradiation at 140° C. for 7 minunder nitrogen atmosphere. The resultant was partitioned between aqueoussolution of potassium dihydrophosphoric acid and ethyl acetate. Theorganic layer was washed with saturated brine, and then concentratedunder reduced pressure. The resulting residues were purified by thinlayer chromatography (MeOH/DCM). The resulting solid was dissolved inMeOH (1 ml), and then added with 1 N HCl (3 drops). The resultingmixture was stirred at 60° C. for 2 hrs. The reaction solution wasconcentrated under reduced pressure, and the residues obtained therefromwere suspended and washed with DCM/hexane (2/1) followed by drying toobtain the title compound as a yellow solid (8.7 mg).

LCMS: m/z 435 [M+H]⁺

HPLC retention time: 1.76 min (analysis condition A)

The compounds described in the following Table 41 were also synthesizedin the same manner.

TABLE 41 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1185 GT20-6

8-((R)-2,3-Dihydroxy-propoxy)- 3-(1-methoxymethyl-1H-imidazol-2-yl)-6,6- dimethyl-5,6-dihydro- benzo[b]carbazol-11-one B2.63 462.0 1186 GT20-7

8-((R)-2,3-Dihydroxy- propoxy)-3-(1H-imidazol-2-yl)-6,6-dimethyl-5,6-dihydro- benzo[b]carbazol-11-one B 2.45 418.5

Example 1187 Compound GT20-88-((R)-2,3-Dihydroxy-propoxy)-3-methoxymethyl-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-oneand Compound GT20-98-((R)-2,3-Dihydroxy-propoxy)-3-hydroxymethyl-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (200.2 mg,0.426 mmol), palladium acetate (II) (19 mg, 0.0848 mmol), hexacarbonylmolybdenum (115.5 mg, 0.438 mmol) and tris(o-tolyl)phosphine (52.5 mg,0.172 mmol) were dissolved in THF (1.3 ml) and ethanol (0.075 ml), addedwith DBU (0.195 ml), and subjected to microwave irradiation at 160° C.for 15 min under nitrogen atmosphere. The resulting reaction solutionwas partitioned between aqueous solution of potassium dihydrophosphoricacid and ethyl acetate. The organic layer was washed with saturatedbrine, and then concentrated under reduced pressure. The resultingresidues were dissolved in ethanol (10 ml) and THF (3 ml), added with 2N KOH (2 ml), and stirred at room temperature for 2 hrs, at 50° C.overnight and at 70° C. for 2 hrs. The reaction solution was partitionedbetween aqueous solution of potassium dihydrophosphoric acid and ethylacetate. The organic layer was washed with saturated brine, and thenconcentrated under reduced pressure. The resulting residues weresuspended and purified with MTBE/hexane (1/1) (155.4 mg). The THFsolution (1.5 ml) of the product (109 mg) was added with TEA (0.052 ml,0.373 mmol) and ethyl chloroformate (0.029 ml, 0.303 mmol) under icecooling, and the mixture was stirred at 0° C. for 2 hrs. Subsequently,ethanol (1 ml) and sodium borohydride (75.7 mg, 2.0 mmol) were added tothe mixture, which was then stirred at room temperature for 2 hrs. Thereaction solution was partitioned between aqueous solution of potassiumdihydrophosphoric acid and ethyl acetate. The organic layer was washedwith saturated brine, and then concentrated under reduced pressure. Theresulting residues were purified by silica gel column (MeOH/DCM) (35.2mg). Thus-obtained solid (9.6 mg) was dissolved in MeOH (1 ml), addedwith 1 N HCl (3 drops), and the mixture was stirred at 60° C. for 90min. After cooling and concentration under reduced pressure, theresultant was purified by TLC (MeOH/DCM) to obtain Compound GT20-8 (6.2mg, white solid) and Compound GT20-9 (4.3 mg, white solid).

Compound GT20-8

LCMS: m/z 396 [M+H]⁺

HPLC retention time: 1.66 min (analysis condition A)

Compound GT20-9

LCMS: m/z 382 [M+H]⁺

HPLC retention time: 1.37 min (analysis condition A)

Example 1188 Compound GT21-18-[(E)-2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-vinyl]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

To the DMF solution (4 ml) of trifluoro-methanesulfonic acid6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yl ester(300 mg), 2,2-dimethyl-4-vinyl-[1,3]dioxolane (469 mg) and PdCl₂(PPh₃)₂(103 mg), sodium hydrocarbonate (184 mg) was added, and the mixture wasstirred at 100° C. overnight under nitrogen atmosphere. The reactionmixture was diluted with ethyl acetate. The organic layer was washedwith saturated aqueous solution of sodium bicarbonate and saturatedbrine, and then concentrated under reduced pressure. The resultingresidues were purified by silica gel column (ethyl acetate/hexane) toobtain the title compound (130 mg, 46%).

LCMS: m/z 389 [M+H]⁺

HPLC retention time: 3.28 min (analysis condition Y)

Example 1189 Compound GT21-28-(3,4-Dihydroxy-butyl)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

To the MeOH solution (5 ml) of8-[(E)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-vinyl]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one(125 mg), 10% Pd-C (25 mg) was added and the mixture was stirredovernight at room temperature under hydrogen atmosphere. The catalystwas removed by filtration. The residues obtained after concentrationunder reduced pressure were purified by HPLC to obtain the titlecompound (35 mg, 31%).

LCMS: m/z 351 [M+H]⁺

HPLC retention time: 1.79 min (analysis condition Y)

Example 1190 Compound GT21-38-Amino-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one

To trifluoro-methanesulfonic acid6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yl ester(100 mg), benzhydrylideneamine (0.05 ml), cesium carbonate (110 mg),palladium acetate (2 mg) and BINAP (7 mg), THF (2 ml) was added. Themixture was stirred and heated at 65° C. overnight under nitrogenatmosphere, and the reaction mixture was diluted with ethyl acetate. Theorganic layer was washed with saturated aqueous solution of sodiumbicarbonate and saturated brine, and then concentrated under reducedpressure. The resulting residues were purified by silica gel column(ethyl acetate/hexane) to obtain the title compound (16 mg, 23%).

LCMS: m/z 278 [M+H]⁺

HPLC retention time: 2.52 min (analysis condition Y)

Example 1191 Compound GT21-4 8-[((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

The mixture comprising8-amino-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (50 mg),(R)-4-iodomethyl-2,2-dimethyl-[1,3]dioxolane (104 mg), potassiumcarbonate (150 mg) and DMF (2 ml) was stirred and heated at 160° C. for2 days under nitrogen atmosphere. The reaction mixture was diluted withethyl acetate. The organic layer was washed with water and saturatedbrine, and then concentrated under reduced pressure. The resultingresidues were purified by silica gel column (ethyl acetate/hexane). Tothe compound (71 mg) obtained therefrom, THF (1 ml) and conc.hydrochloric acid (8 drops) were added and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was added with saturatedaqueous solution of sodium bicarbonate and then diluted with ethylacetate. The organic layer was washed with saturated aqueous solution ofsodium bicarbonate and saturated brine, and then concentrated underreduced pressure. The resulting residues were purified by silica gelcolumn (ethyl acetate/hexane) to obtain the title compound (34 mg, 51%).

LCMS: m/z 392 [M+H]⁺

HPLC retention time: 3.11 min (analysis condition Y)

Example 1192 Compound GT21-58-((S)-2,3-Dihydroxy-propylamino)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

In the same manner as Compound A7-14-2, Compound GT21-4 was deprotectedto obtain the title compound.

LCMS: m/z 352 [M+H]⁺

HPLC retention time: 2.26 min (analysis condition Y)

Example 1193 Compound GT22-18-(2-Diethylamino-ethoxy)-6,6-dimethyl-3-propyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

To the mixture of trifluoro-methanesulfonic acid8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-3-ylester (15 mg), which had been obtained in the same manner as CompoundA7-25, tris(1-methyl-3-oxo-1-butenyloxy) iron (III) (1 mg), NMP (0.3 ml)and THF (0.3 ml), n-PrMgBr (0.88 M, THF solution, 0.291 ml) and zincchloride (0.5 M THF solution, 0.114 ml) were added at 0° C. undernitrogen atmosphere, and the mixture was stirred at 0° C. for 10 min.The reaction mixture was added with water and extracted with ethylacetate. The organic layer was washed with saturated brine, and thenconcentrated under reduced pressure. The resulting residues werepurified by silica gel column (ethyl acetate/hexane) to obtain the titlecompound (4.5 mg, 38%).

LCMS: m/z 420 [M+H]⁺

HPLC retention time: 5.77 min (analysis condition H)

Example 1194 Compound GT22-28-(2-Diethylamino-ethoxy)-3-ethyl-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

In the same manner as Compound GT22-2, the title compound wassynthesized.

LCMS: m/z 406 [M+H]⁺

HPLC retention time: 5.12 min (analysis condition B)

Example 1195 Compound GT23-13-Bromo-8-methoxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d] furan-11-one

8-Methoxy-6,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-6H-benzo[b]naphtho[2,3-d]furan-11-one(10.3 mg), which had been synthesized from Compound Z12 under the sameconditions as the method for synthesizing Compound GT20-5, was mixedwith copper (II) bromide (16.5 mg), MeOH (0.5 ml) and water (0.25 ml),and the mixture was stirred and heated at 70° C. for 2 hrs. DCM wasadded to the reaction solution for extraction. The organic layer wasconcentrated and purified by silica gel column to obtain the titlecompound (9.4 mg).

LCMS: m/z 371 [M+H]⁺

HPLC retention time: 7.55 min (analysis condition B)

Example 1196 Compound GT23-23-Bromo-8-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

In the same manner as Compound GT15-5,3-bromo-8-methoxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one wasdeprotected to obtain the title compound.

LCMS: m/z 357 [M+H]⁺

HPLC retention time: 2.82 min (analysis condition A)

The compounds described in the following Table 42 were synthesized fromCompound GT23-2 according to the method given in the Table.

TABLE 42 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z Method 1197 GT23-3

3-Bromo-6,6-dimethyl- 8-((2R,3R)-2,3,4- trihydroxy-butoxy)-6H-benzo[b]naphtho[2,3-d] furan-11-one D 2.30 461.0 T22-1- 1 T22-2 1198GT23-4

3-Bromo-8-((R)-2,3- dihydroxy-propoxy)- 6,6-dimethyl-6H- benzo[b]naphtho[2,3-d]furan-11-one A 5.42 431.0 A7-14- 1 A7-14- 2 1199 GT23-5

3-Bromo-8- (2-diethylamino- ethoxy)-6,6- dimethyl-6H- benzo[b]naphtho[2,3-d] furan-11-one H 5.37 456.0 A7-17

Example 1200 Compound GT24-18-((R)-2,3-Dihydroxy-propoxy)-3-iodo-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

To 3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (15 mg,0.032 mmol), CuI (6.2 mg, 0.032 mmol), NaI (9.6 mg, 0.064 mmol) andtrans-N,N′-dimethylcyclohexane-1,2-diamine (0.01 ml) were added and themixture was stirred for 48 hrs under nitrogen atmosphere. The reactionsolution was diluted with ethyl acetate. The organic layer was washedwith saturated brine, and then concentrated under reduced pressure. Theresulting residues were purified by silica gel column (ethylacetate/hexane) to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-iodo-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (16mg, 97%), which was then deprotected according to the method of A-14-2to give the title compound.

LCMS: m/z 479 [M+H]⁺

HPLC retention time: 4.26 min (analysis condition A)

Example 1201 Compound GT24-23-Iodo-6,6-dimethyl-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6H-benzo[b]naphtho[2,3-d]furan-11-one

In the same manner as Compound GT24-1,3-iodo-8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one wassynthesized from3-bromo-8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one.Subsequently, according to the same method as Compound T22-2,deprotection was carried out to obtain the title compound.

Example 1202 Compound GT25-16,6-Dimethyl-8-(4-methyl-piperazine-1-sulfonyl)-6H-benzo[b]naphtho[2,3-d]furan-11-one

By using the method for preparing Compound B1, trifluoro-methanesulfonicacid 6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-ylester was prepared from8-hydroxy-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one. Thistrifluoromethanesulfonic acid ester (205 mg), (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino] ethyl]-2-(dicyclohexylphosphino)ferrocene(13 mg), palladium acetate (6 mg), 2-trimethylsilanyl-ethanethiol (90μL) and potassium carbonate (85 mg) were reacted in DME to obtain aproduct (120 mg). To the benzyl alcohol solution (90 μL) of the product(50 mg), DCM solution of N-chlorosuccinimide (90 mg) was added, and themixture was stirred at room temperature. The reaction solution waspartitioned between water and ethyl acetate, and the organic layer wasconcentrated under reduced pressure. To the DCM solution ofthus-obtained white solid, N-methylpiperazine (10 μL) was added and themixture was stirred. The residues obtained after removing the solvent bydistillation were purified by TLC to obtain the title compound as awhite solid (6 mg).

Example 1203 Compound GT26-1 (2-Bromo-5-methoxy-phenyl)-acetonitrile

To the THF solution (1000 ml) of 2-bromo-5-methoxy-benzoic acid methylester (20 g, 81.6 mmol), the THF suspension (50 ml) of LAH (4.07 g, 102mmol) was added under ice cooling. The mixture was stirred for 30 minunder ice cooling. The reaction solution was partitioned betweensaturated aqueous solution of Na₂SO₄ and ethyl acetate. The organiclayer was washed with saturated brine and concentrated under reducedpressure. The resulting residues were dissolved in DCM (200 ml), andadded with TEA (12.51 ml, 89.76 mmol) and MsCl (6.63 ml, 85.68 mmol)under ice cooling, followed by stirring overnight at room temperature.The reaction mixture was diluted with DCM, and washed in order with 10%aqueous solution of citric acid, saturated aqueous solution of NaHCO₃andsaturated brine. The residues obtained after concentration under reducedpressure were dissolved in DMF (100 ml), and added with the DMF (500 ml)solution of NaCN (40 g, 81.6 mmol) under ice cooling. After stirring for2 hrs under ice cooling, the reaction mixture was extracted with ether,washed with saturated brine and dried over magnesium sulfate. Theresidues obtained after concentration under reduced pressure werepurified by silica gel column (hexane:ethyl acetate=10:1) to obtain thetitle compound (12.1 g, 67%).

¹H-NMR (400 MHz, CDCl₃) δ 3.82 (s, 3H), 6.77 (d, 1H), 7.07 (s, 1H), 7.47(d, 1H)

Example 1204 1-(2-Bromo-5-methoxy-phenyl)-cyclopropane carbonitrileCompound GT26-2

2-Bromo-5-methoxy-phenyl)-acetonitrile (12.2 g, 53.97 mmol) wasdissolved in toluene (50 ml), and added with tetrabutylammonium bromide(3.55 g, 10.79 mmol), dibromoethane (7.05 ml, 80.95 mmol) and 50%aqueous solution of NaOH (50 ml) at room temperature. The mixture wasstirred at room temperature for 4 hrs. The reaction mixture was addedwith water and extracted with ethyl acetate. The residues obtained afterconcentration under reduced pressure were purified by silica gel column(hexane:ethyl acetate) to obtain the title compound (11.18 g, 82%).

¹H-NMR (400 MHz, CDCl₃) δ 1.33 (t, 1H), 1.76 (t, 1H), 3.79 (s, 3H),6.75-6.79 (m, 1H), 6.89 (d, 1H), 7.47 (d, 1H)

Example 1205 1-(2-Bromo-5-methoxy-phenyl)-cyclopropane carboxylic acidCompound GT26-3

1-(2-Bromo-5-methoxy-phenyl)-cyclopropane carbonitrile (3.0 g, 11.9mmol) was dissolved in ethylene glycol (30 ml). After adding KOH (2.1 g,33.3 mmol) thereto, the mixture was stirred and heated at 180° C. for 7hrs. After cooling, the reaction mixture was added with 1 N HCl (90 ml).The reaction mixture was extracted with ether, washed with water andsaturated brine and dried over magnesium sulfate. After concentrationunder reduced pressure, the title compound was obtained (12.3 g, 72%).

LCMS: m/z 272 [M+H]⁺

HPLC retention time: 2.03 min (analysis condition Y)

Example 1206 Compound GT26-42-[1-(2-Bromo-5-methoxy-phenyl)-cyclopropyl]-benzofuran

To the DCM solution (6 ml) of 1-(2-bromo-5-methoxy-phenyl)-cyclopropanecarboxylic acid (0.3 g, 1.1 mmol), DMF (2 drops) and oxalyl chloride(0.23 ml, 2.5 mmol) were added at room temperature, and the mixture wasstirred at room temperature for 2 hrs. The residues obtained from thereaction solution after concentration under reduced pressure weredissolved in toluene (6 ml), added with(2-hydroxybenzyl)triphenylphosphonium bromide (0.605 g, 1.32 mmol) andTEA (0.46 ml, 3.3 mmol), and the resulting mixture was stirred andheated at 100° C. overnight. The residues obtained after concentrationunder reduced pressure were purified by silica gel column (hexane:DCM)to obtain the title compound (0.309 g, 81%).

LCMS: m/z 343 [M+H]⁺

HPLC retention time: 3.55 min (analysis condition Y)

Example 1207 Compound GT26-52-(1-Benzofuran-2-yl-cyclopropyl)-4-methoxy-benzoic Acid

To the THF solution (3 ml) of2-[1-(2-bromo-5-methoxy-phenyl)-cyclopropyl]-benzofuran (0.259 g, 0.75mmol), n-BuLi was added at −78° C., and the mixture was stirred at −78°C. for 20 min. Thereafter, the mixture was flushed with carbon dioxidegas. The reaction mixture was added with saturated solution of NH₄Cl andextracted with ethyl acetate. The residues obtained after concentrationunder reduced pressure were purified by silica gel column (DCM:MeOH) toobtain the title compound (0.163 g, 70%).

LCMS: m/z 309 [M+H]⁺

HPLC retention time: 2.67 min (analysis condition Y)

Example 1208 Compound GT26-68-Methoxy-11H-spiro[benzo[d]naphtho[2,3-b]furan-6,1′-cyclopropan]-11-one

To the DCM solution (10 ml) of2-(1-benzofuran-2-yl-cyclopropyl)-4-methoxy-benzoic acid (1.0 g, 3.24mmol), trifluoroacetic acid anhydride (0.45 ml, 3.24 mmol) was added at−78° C., and the mixture was stirred at −78° C. for 10 min, at −50° C.for 10 min, and at −30° C. for 20 min. Thereafter, the mixture was addedwith water and extracted with DCM. The residues obtained afterconcentration under reduced pressure were washed with DCM and hexane toobtain the title compound (0.163 g, 70%).

LCMS: m/z 291 [M+H]⁺

HPLC retention time: 2.90 min (analysis condition Y)

Example 1209 Compound GT26-78-(2-(Diethylamino)ethoxy)-11H-spiro[benzo[d]naphtho[2,3-b]furan-6,1′-cyclopropan]-11-one

In the same manner as Compound A6 and Compound A7-17, the title compoundwas obtained from8-methoxy-11H-spiro[benzo[d]naphtho[2,3-b]furan-6,1′-cyclopropan]-11-one.

LCMS: m/z 376 [M+H]⁺

HPLC retention time: 1.65 min (analysis condition Y)

Example 1210 Compound GT27-12-(2-Bromo-5-methoxy-phenyl)-2-ethyl-butyric Acid

(2-Bromo-5-methoxy-phenyl)-acetic acid methyl ester (3.51 g, 13.5 mmol)was dissolved in DMF (4.5 ml), and added with NaH (2.1 g, 67.7 mmol).Subsequently, 15-crown-5 (1.38 ml, 6.8 mmol) and EtI (5.5 ml, 67.7 mmol)cooled to 0° C. were added to the mixture. The mixture was diluted withethyl acetate and washed with water and saturated brine. The residuesobtained after concentration under reduced pressure were purified bysilica gel column (hexane-ethyl acetate). Then, the resultant wasdissolved in ethanol (80 ml) and water (80 ml), added with KOH (91 g),and stirred at 140° C. The reaction solution was extracted with ethylacetate, and washed with water and saturated brine. After concentrationunder reduced pressure, the target compound was obtained (10.62 g, 78%).

LCMS: m/z 301 [M+H]⁺

HPLC retention time: 3.07 min (analysis condition Y)

Example 1211 Compound GT27-22-(2-Bromo-5-methoxy-phenyl)-2-ethyl-butyric Acid o-Tolyl Ester

Compound GT27-1 (0.5 g, 1.66 mmol) was dissolved in DCM (10 ml), addedwith DMF (2 drops) and oxalyl chloride (0.28 ml, 3.32 mmol), and themixture was stirred for 2 hrs. The reaction mixture obtained afterconcentration under reduced pressure was dissolved in toluene (5 ml),added with DMAP (406 mg, 3.32 mmol), and the mixture was heated underreflux. The reaction mixture was extracted with ethyl acetate, washedwith 1 N HCl, and saturated brine. The residues obtained afterconcentration under reduced pressure were purified by silica gel column(hexane-ethyl acetate) to obtain the target compound (0.36 g, 86%).

LCMS: m/z 393 [M+H]⁺

HPLC retention time: 3.03 min (analysis condition Y)

Example 1212 Compound GT27-32-(2-Bromo-5-methoxy-phenyl)-2-ethyl-butyric acid2-[(triphenyl-phosphanyl)-methyl]-phenyl Ester Bromate Salt

Compound GT27-2 (0.118 g, 0.302 mmol) was dissolved in carbontetrachloride (3 ml), added with N-bromosuccinimide (54 mg, 0.302 mmol),and the mixture was heated under reflux. The reaction mixture wasconcentrated under reduced pressure and the resulting residues werepurified by silica gel column (ethyl acetate-hexane). The product wasdissolved in toluene (3 ml), added with PPh₃ (77 mg, 0.302 mmol), andthe mixture was heated under reflux. The reaction mixture wasconcentrated under reduced pressure to obtain the target compound (130mg, 57%).

Example 1213 Compound GT27-42-[1-(2-Bromo-5-methoxy-phenyl)-1-ethyl-propyl]-benzofuran

To the toluene solution (3 ml) of Compound GT27-3 (0.14 g, 0.137 mmol),toluene solution (0.16 ml, 0.164 mmol) of 1 M LiHMDS was added. Themixture was heated and stirred for 4 hrs. The reaction mixture wasconcentrated under reduced pressure and the resulting residues werepurified by silica gel column (ethyl acetate:hexane) to obtain the titlecompound (28 mg, 35%).

LCMS: m/z 373 [M+H]⁺

HPLC retention time: 2.73 min (analysis condition Y)

Example 1214 Compound GT27-58-(2-Diethylamino-ethoxy)-6,6-diethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one

In the same manner as Compound A7-17, the title compound was obtainedfrom Compound GT27-4.

LCMS: m/z 407 [M+H]⁺

HPLC retention time: 1.92 min (analysis condition Y)

Example 1215 Compound GT27-68-((R)-2,3-Dihydroxy-propoxy)-6,6-diethyl-6H benzo[b]naphtho[2,3-d]furan-11-one

In the same manner as Compound A7-14-1 and Compound A7-14-2, the titlecompound was obtained from Compound GT27-4.

LCMS: m/z 381 [M+H]⁺

HPLC retention time: 2.38 min (analysis condition Y)

The compounds described in the following Table 43 were synthesizedaccording to the method shown below. According to the method used forthe preparation of Compound Z10, Z11 and Z12,3-chloro-8-methoxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was preparedfrom Compound A2 and 2-bromo-5-chlorophenol. Subsequently, demethylationwas carried out according to the method that is used for the preparationof Compound A6, and thus3-chloro-8-hydroxy-6H-benzo[b]naphtho[2,3-d]furan-11-one was obtained.Thereafter, according to Mitsunobu reaction that is used for thepreparation of Compound A7-1 or the alkylation method that is used forthe preparation of A7-17, a corresponding side chain was introduced and,if necessary, functional group modification such as deprotection, etc.was carried out to prepare the compounds listed below.

TABLE 43 Example Comp. HPLC Retention No. No. Structure Compound NameCondition Time m/z 1216 GT28-1

3-Chloro-8-(2-diethylamino-ethoxy)- 6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one F 2.52 412.0 1217 GT28-2

3-Chloro-6,6-dimethyl-8-((2R,3R)- 2,3,4-trihydroxy-butoxy)-6H-benzo[b]naphtho[2,3-d]furan-11-one H 5.39 417.0 1218 GT28-3

3-Chloro-8-((R)-2,3-dihydroxy- propoxy)-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one H 5.77 387.0

Pharmacological Testing Method 1. Activity of Inhibiting ALK Enzyme

ALK-inhibiting activity was measured by following an activity ofinhibiting phosphorylation by biotinylated peptide (EGPWLEEEEEAYGWMDF).For the detection of phosphorylation of the biotinylated peptide,time-resolved fluorescence measurement was performed using ananti-phosphorylated tyrosine antibody labeled with europium cryptate andstreptavidin conjugated to XL665, i.e., an allophycocyanin derivative.From the inhibition ratio compared to the control group that does notcomprise a test compound, 50% inhibitory concentration (i.e., IC₅₀value) was calculated.

2. Measurement of an Activity of Inhibiting Karpas-299 Cell Growth

The test compounds were serially diluted with dimethyl sulfoxide,further diluted with phosphate buffered saline which is free of anyCa²⁺, Mg²⁺ (×50 dilution), and 10 μL of the resulting solution wasaliquoted in a 96-well plate. Human lymphoma cell line KARPAS-299 wasprepared in RPMI-1640 medium to which 10% bovine fetal serum was addedto give a cell suspension with the cell density of 10,000 cells/190 μL.The resulting cell suspension was aliquoted to the plate (190 μL perwell) to which the test compound had been already added, and the platewas kept in a 5% carbon dioxide gas incubator at 37° C. Ninety-six hourslater, 10 μL of WST-8 (manufactured by Dojindo Laboratories) was addedto each well, and subsequently the absorbance was measured at 450 nm.From the ratio of inhibition on cell growth which had been obtained fromthe addition of a test compound compared to the control group with noaddition, 50% growth inhibitory concentration (i.e., IC₅₀ value) of thetest compound was calculated. The results are summarized in Tables44-49.

TABLE 44 Inhibitory activity ALK-inhibiting on Karpas-299 activity IC₅₀cell growth IC₅₀ Examples (μM) (μM)  123 (Compound B2-27) 0.00228 0.0138 177 (Compound B4-7) 0.00084 0.0105  178 (Compound B4-8) 0.00153 0.0214 304 (Compound F5-11) 0.00081 0.0061  338 (Compound F5-43) 0.000320.0086  341 (Compound F5-46) 0.01056 0.0289  364 (Compound F6-18)0.00177 0.0231  366 (Compound F6-20) 0.0053 0.0093  372 (Compound G6)0.03074 0.1682  380 (Compound H6-2) 0.00053 0.0062  429 (CompoundJ7-10-2) 0.00083 0.0303  543 (Compound O8-5) 0.00032 0.03  550 (CompoundO9-7) 0.00090 0.0044  735 (Compound Z7) 0.09385 1.1924  516 (CompoundN6-2) 0.003906748 0.0248  725 (Compound X5) 0.687683357 2.8765  882(Compound AZ7-10) 0.000493765 0.005769  916 (Compound DZ7-1) 0.0018366590.357381  937 (Compound EZ9-3) 0.006473484 0.056914  939 (CompoundEZ9-5) 0.399865279 13.421227 1175 (Compound GT18-4) 0.093 2.012

TABLE 45 ALK-inhibiting Example activity IC₅₀ No. Compound (μM)  13 A7-10.052707597  14 A7-2 0.006159417  38 A7-20 0.026183852  39 A7-210.017713716  40 A7-22 0.030434111  41 A7-23 0.029469872  45 A8-20.008009528  47 A8-4 0.010253392  51 A8-6-3 0.097920152  52 A8-70.045959643  55 A8-10 0.00673264  57 A8-12 0.003594618  63 A8-180.016005139  65 A8-20 0.0029  67 A9-1 0.004943  70 A9-3-2 0.007649647 73 A9-6-2 0.001398207  74 A9-7 0.0034607  76 A9-9 0.017148495  78 A9-110.051123952  79 A9-12 0.017501168  83 A9-15-2 0.0035  84 A9-16 0.08468 90 B2-1 0.033572 100 B2-9 0.016225317 101 B2-10 0.039433518 102 B2-110.072607257 104 B2-13 0.001681324 109 B2-16-3 0.000980809 117 B2-230.005436966 118 B2-24 0.014834642 122 B2-26-2 0.007278245 124 B2-280.059632226 128 B3-2-2 0.003183521 130 B3-4 0.063798146 135 B3-90.01492317 137 B3-11 0.071084446 141 B3-14 0.011893599 142 B3-150.030133825 143 B3-16 0.027324427 146 B3-19 0.010369469 147 B3-200.026851192 149 B3-22 0.272356381 150 B3-23 0.023088404 151 B3-240.003610645 157 B3-27-2 0.002114607 158 B3-28 0.042375341 159 B3-290.006002322 165 B3-34 0.006783031 166 B3-35 0.003473067 168 B3-370.011859342 179 B4-9 0.002000975 187 CC4-2 0.096115639 189 C1-10.051102036 206 C4-9 0.005101172 210 C4-13 0.008752733 212 C4-150.009616778 226 D1 0.000991134 227 D2 0.003611773 228 D3-1 0.006279559245 E4-5 0.009450575 256 E5-2 0.00133756 264 E6-2 0.006668071 265 E6-30.008113087 268 F1-3 0.005054399 277 F3-6-2 0.000167996 283 F4-1-10.001625048 286 F4-3 0.000951804 290 F4-7 0.001133931 293 F4-100.002098847 298 F5-5 0.002385717 300 F5-7 0.002575475 306 F5-130.002051837 314 F5-20 0.000996109 319 F5-25 0.000881378 322 F5-280.01227125 331 F5-36-2 0.001778367 334 F5-39 0.014824288

TABLE 46 ALK-inhibiting Example activity IC₅₀ No. Compound (μM) 340F5-45 0.000579745 346 F5-51 0.002610782 350 F6-4 0.00715425 353 F6-70.020276801 355 F6-9 0.001092627 358 F6-12 0.015047658 359 F6-130.000399685 389 H9-3 0.002622129 403 I6-4 0.000391036 407 I7-10.001863642 421 J7-3 0.015290853 422 J7-4 0.004631153 423 J7-50.012009506 424 J7-6 0.001570404 426 J7-8 0.001170682 431 J7-11-20.01172814 435 J7-15 0.02319 437 J7-17 0.007091939 438 J8-1 0.012517614443 J8-6 0.00396 455 JJ5 0.862941682 458 JJ7-2 0.028993627 461 JJ9-10.004337558 465 JJ10-1 0.492725332 472 K6 0.029284532 486 K10-50.000589765 501 L10-2 0.00160 508 M6-2 0.006136762 517 N6-3 0.03272871519 N6-5 0.026853329 531 O5-4 0.00431 546 O9-3 0.00086 571 Q80.005719259 579 R8-2 0.000769618 591 S4 1.664818863 599 S8-2 0.04064 601S9-2 0.000456356 607 T2-1 0.432812267 618 T6-1 0.614075453 621 T6-40.341433432 628 T11 0.271479209 630 T12-2 0.15422 633 T13-3 0.16211 637T13-7 0.16821 639 T13-9 0.16189 645 T14-5 0.41327 650 T14-10 0.18923 654T16-1 0.01951 657 T16-4 0.07941 668 T21 0.8521 671 T22-1-1 0.151061541678 T22-7 2.8135 679 T22-8 0.583 686 T26-2 0.08320 702 U8-6-2 0.00260704 U8-7-2 0.00604 706 U8-8-2 0.35976 707 U8-8-3 0.84884 709 U10-10.55215 711 U11 0.00193 720 W4-2 0.13445 730 Y5-2 0.554738402 751 K10-100.0085 753 K10-12 0.0022 755 K10-14 0.0118 758 K10-17 0.1422 760 K10-190.0015 762 L10-3 0.0099 770 L10-11 0.0231 776 B3-42 0.0042 786 E9-40.0004 790 E9-8 0.0075 796 F4-11 0.0003 822 PR11-6 0.0003 823 PR11-70.0003 824 PR9-9 0.0142 829 PR9-13 0.0007 832 PR11-11 0.0006 846 PR9-250.021743738 847 PR11-14 0.001890642

TABLE 47 ALK-inhibiting Example activity IC₅₀ No. Compound (μM)  849PR11-16 0.000813047  864 LB5-1 0.424843491  866 LB5-3 2.398295  875AZ7-3 0.113911239  892 AZ7-20 0.009369855  893 AZ7-21 0.142933634  920DZ7-5 0.326374265  938 EZ9-4 0.300760062  949 GT2-6 1.3255  956 GT2-130.1617  960 GT3-2 5.9473  962 GT3-4 1.0829  963 GT3-5 4.224  967 GT3-90.8981  970 GT3-12 1.6214  972 GT4-1 0.29  973 GT4-2 0.104  981 GT5-82.9743  982 GT5-9 21.3078  983 GT5-10 3.2  994 GT5-21 1.2466  995 GT6-112.9519  996 GT6-2 12.9704  997 GT6-3 0.575  998 GT6-4 4.3855  999 GT6-53.9 1000 GT6-6 5.4 1001 GT6-7 3.7 1004 GT6-10 0.9 1005 GT6-11 1.43851007 GT6-13 0.7526 1008 GT6-14 4.8429 1013 GT8-3 0.93 1017 GT9-3 0.37851019 GT9-5 0.77 1030 GT11-8 5.9346 1031 GT11-9 7.7947 1034 GT11-12 2.0761035 GT11-13 1.6274 1039 GT11-17 0.7938 1042 GT11-20 0.5083 1043 GT11-212.2822 1047 GT11-25 1.9038 1048 GT11-26 5.3708 1050 GT11-28 3.2813 1051GT11-29 1.811 1052 GT11-30 4.0931 1054 GT11-32 7.0451 1059 GT11-372.7739 1060 GT11-38 1.1587 1061 GT11-39 1.0914 1065 GT11-43 3.7028 1066GT11-44 3.1203 1072 GT11-50 3.3428 1073 GT11-51 2.547 1074 GT11-521.2588 1081 GT11-59 1.0586 1083 GT11-61 0.7928 1085 GT11-63 0.9013 1086GT11-64 0.3127 1087 GT11-65 0.206 1090 GT12-3 0.8541 1096 GT12-9 5.75711102 GT13-3 0.4209 1105 GT13-6 0.3894 1113 GT13-14 0.1571 1114 GT13-150.7 1117 GT13-18 2.2 1118 GT13-19 0.5 1119 GT13-20 0.42 1125 GT13-260.028 1126 GT13-27 3.0645 1127 GT13-28 5.6311 1128 GT13-29 17.4641 1129GT13-30 0.51 1130 GT13-31 0.54 1164 GT16-5 0.4149 1177 GT18-6 0.75271185 GT20-6 1.8

TABLE 48 Inhibitory activity on Karpas-299 Example cell growth IC₅₀ No.Compound (μM)  15 A7-3 0.1138  17 A7-5 0.6268  19 A7-7 0.3293  21 A7-90.2037  22 A7-10 0.3031  25 A7-12 0.1119  46 A8-3 0.0866  56 A8-110.0677  58 A8-13 0.0226  60 A8-15 0.2322  61 A8-16 0.0345  62 A8-170.1269  64 A8-19 0.0726  66 A8-21 0.1050  68 A9-2 0.1372  72 A9-5 0.0523 93 B2-4 0.0365 138 B3-12 1.4358 154 B3-25-3 0.7298 155 B3-26 1.3613 160B3-30 0.2282 163 B3-32 0.0652 167 B3-36 0.0390 174 B4-4 0.0812 229 D3-20.9700 230 D3-3 0.1320 244 E4-4 0.1090 257 E5-3 0.1895 260 E5-6 0.0527273 F3-3 0.0162 287 F4-4 0.0071 289 F4-6 0.0291 291 F4-8 0.0221 292 F4-90.0650 294 F5-1 0.0091 297 F5-4 0.0018 301 F5-8 0.0297 302 F5-9 0.0043303 F5-10 0.0135 309 F5-15-2 0.0098 310 F5-16 0.0042 315 F5-21 0.0663316 F5-22 0.0066 323 F5-29 0.0076 325 F5-31 0.0727 326 F5-32 0.0240 335F5-40 0.0256 336 F5-41 0.1491 339 F5-44 0.0060 348 F6-2 0.0295 351 F6-50.0274 352 F6-6 0.0364 357 F6-11 0.0776 359 F6-13 0.0079 420 J7-2-30.0295 434 J7-14 0.5567 446 J9-3 0.0532 467 JJ10-3 6.0632 488 K10-70.0518 518 N6-4 0.1224 562 P5 27.7670 605 T1-1 1.8669 636 T13-6 1.2901640 T13-10 1.3775 642 T14-2 0.6324 646 T14-6 1.9418 649 T14-9 1.08 656T16-3 2.25 672 T22-1-2 1.7820 680 T23-1 4.2526 681 T23-2 7.0799 688T27-2 0.9970 689 U5 0.1217 695 U8-3-2 0.6773 698 U8-4-3 1.10 700 U8-5-20.3573 708 U9 0.4070 710 U10-2 0.94

TABLE 49 Inhibitory activity on Karpas-299 Example cell growth IC₅₀ No.Compound (μM)  764 L10-5 0.019  766 L10-7 0.037  767 L10-8 0.024  769L10-10 0.159  773 B3-40 0.022  787 E9-5 0.041  792 E9-9 0.004  793PR11-20 0.020313  794 PR11-21 0.06439  827 PR9-11 0.036  839 PR9-200.018772  844 PR9-23 0.020492  845 PR9-24 0.067888  850 PR11-17 0.005766 852 PR11-19 0.034632  865 LB5-2 1.287666  878 AZ7-6 1.126471  896AZ7-24 0.054  935 EZ9-1 16.635  941 W4-4 0.116  976 GT5-3 1.868  979GT5-6 8.231  980 GT5-7 17.135  984 GT5-11 1.957  985 GT5-12 19.989  986GT5-13 1.332  987 GT5-14 3.787  990 GT5-17 2.359  991 GT5-18 4.255  993GT5-20 6.081 1020 GT9-6 2.655 1115 GT13-16 7.875 1123 GT13-24 3.951 1124GT13-25 5.511 1131 GT13-32 2.501 1132 GT13-33 10.887

1. A compound or salt or solvate thereof represented by Formula (I):

wherein, A¹, A², A³, A⁴, A⁷, A⁸, A⁹ and A¹⁰ all represent C, or any oneof A², A³, A⁴, A⁷, A⁸ and A⁹ represents N (with the proviso that, whenit represents N, no substituent group exists therefor) and theremainings represent C; A⁵ is selected from NR⁵, O and S; R¹ and R¹⁰each independently represent [1] a hydrogen atom, [2] a cyano group, [3]a halogen atom or [4] a 4- to 10-membered heterocycloalkyl group whichmay be substituted by 4- to 10-membered heterocycloalkyl group(s); R² isselected from the group consisting of: (1) a hydrogen atom, (2) a C₁₋₈alkyl group, (3) a C₂₋₈ alkenyl group, (4) a C₂₋₈ alkynyl group, (5) acyano group, (6) a halogen atom, (7) a (C₁₋₈ alkyl)_(m2)-amino groupwhich may be substituted by C₁₋₈ alkylsulfonyl group(s), m2: 0˜2, and(8) a nitro group; R³ is selected from the group consisting of: (1) ahydrogen atom, (2) a C₁₋₈ alkyl group which may be substituted by [1]halogen atom(s), [2]hydroxy group(s) or [3] C₁₋₈ alkoxy group(s), (3) aC₆₋₁₀ aryl group, (4) a cyano group, (5) a C₁₋₈ alkanoyl group which maybe substituted by C₆₋₁₀ aryl group(s), (6) a (C₁₋₈alkyl)_(m3a)-aminocarbonyl group which may be substituted by one or moreR^(3A), R^(3A): [1] a C₆₋₁₀ aryl group, [2] a C₁₋₈ alkoxy group, [3] a5- to 14-membered heteroaryl group, or [4] a C₆₋₁₀ arylsulfonyl group,m3a: 0˜2, (7) a hydroxycarbonyl group, (8) a C₁₋₈ alkoxycarbonyl groupwhich may be substituted by [1] hydroxy group(s) or [2] C₁₋₈ alkoxygroup(s), (9) a halogen atom, (10) a (C₁₋₈ alkyl)_(m3b)-amino groupwhich may be substituted by C₆₋₁₀ aryl group(s), m3b: 0˜2, (11) a C₁₋₈alkylcarbonyl (C₀₋₈ alkyl) amino group which may be substituted by[1]C₆₋₁₀ aryl group(s) or [2] C₆₋₁₀ aryloxy group(s), (12) a C₆₋₁₀arylcarbonyl (C₀₋₈ alkyl) amino group which may be substituted by C₁₋₈alkyl group(s) which may be substituted by halogen atom(s), (13) a (C₁₋₈alkyl)_(m3c)-aminocarbonyl (C₀₋₈ alkyl) amino group which may besubstituted by C₆₋₁₀ aryl group(s), m3c: 0˜2, (14) a nitro group, (15) ahydroxy group, (16) a C₁₋₈ alkoxy group which may be substituted by oneor more R^(3B), R^(3B): [1] a hydroxy group, [2] a C₁₋₈ alkoxy group,[3] a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl group, [4] a (C₁₋₈alkyl)_(m3d)-amino group, or [5] a halogen atom, m3d: 0˜2, (17) a 4- to10-membered heterocycloalkyloxy group, (18) a 5- to 14-memberedheteroaryloxy group, (19) a (C₁₋₈ alkyl)_(m3e)-aminocarbonyloxy groupwhich may be substituted by C₆₋₁₀ aryl group(s) m3e: 0˜2, (20) a 4- to10-membered nitrogen-containing heterocycloalkylcarbonyl group, (21) aC₁₋₈ alkylsulfonyloxy group which may be substituted by halogen atom(s),(22) a C₁₋₈ alkylthio group, (23) a C₁₋₈ alkylsulfonyl group which maybe substituted by C₆₋₁₀ aryl group(s), (24) a 5- to 14-memberedheteroaryl group which may be substituted by C₁₋₈ alkyl group(s) whichmay be substituted by C₁₋₈ alkoxy group(s), (25) a C₁₋₈ alkoxycarbonyl(C₀₋₈ alkyl) amino group which may be substituted by C₁₋₈ alkoxygroup(s), (26) a C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl) amino group whichmay be substituted by C₁₋₈ alkyl group(s) which may be substituted byhalogen atom(s), (27) a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈alkyl) amino group which may be substituted by one or more R^(3C),R^(3C): [1] a C₁₋₈ alkyl group which may be substituted by halogenatom(s), or [2] a C₁₋₈ alkoxy group, (28) a C₃₋₈ cycloalkyl (C₀₋₈ alkyl)aminocarbonyloxy group, and (29) a C₆₋₁₀ aryl (C₀₋₈ alkyl)aminocarbonyloxy group which may be substituted by substituent(s)selected from the group consisting of [1] a C₁₋₈ alkyl group and [2] aC₁₋₈ alkoxy group; R⁴ is selected from the group consisting of: (1) ahydrogen atom, (2) a C₁₋₈ alkyl group which may be substituted byhalogen atom(s), (3) a C₂₋₈ alkenyl group, (4) a C₂₋₈ alkynyl group, (5)a C₃₋₈ cycloalkyl group, (6) a cyano group, (7) an aminocarbonyl group,(8) a (C₁₋₈ alkyl)_(m4a)-aminocarbonyl group, m4a: 1˜2, (9) ahydroxycarbonyl group, (10) a C₁₋₈ alkoxycarbonyl group, (11) a halogenatom, (12) a (C₁₋₈ alkyl)_(m4b)-amino group, m4b: 0˜2, (13) a hydroxygroup, and (14) a C₁₋₈ alkoxy group which may be substituted by hydroxygroup(s); R⁵ is selected from the group consisting of: (1) a hydrogenatom, (2) a C₁₋₈ alkyl group which may be substituted by one or moreR^(5A), R^(5A): [1] a hydroxycarbonyl group, [2] a C₁₋₈ alkoxycarbonylgroup, [3] a hydroxy group, [4] a C₁₋₈ alkoxy group, [5] a (C₁₋₈alkyl)_(m5)-amino group, [6] a C₆₋₁₀ aryl group, or [7] a C₁₋₈ alkylthiogroup, m5: 0˜2, (3) a C₂₋₈ alkenyl group, (4) a C₂₋₈ alkynyl group, (5)a C₃₋₈ cycloalkyl group, and (6) a C₁₋₈ alkylsulfonyl group; R⁶ andR^(6′) are each independently selected from the group consisting of: (1)a C₁₋₈ alkyl group which may be substituted by halogen atom(s), (2) aC₂₋₈ alkenyl group, and (3) a C₂₋₈ alkynyl group; or R⁶ and R^(6′) aretaken together with the carbon atoms to which they are bound to form:(4) a C₃₋₈ cycloalkyl group, or (5) a 4- to 10-membered heterocycloalkylgroup which may be substituted by C₁₋₈ alkyl C₆₋₁₀ aryl sulfonylgroup(s) which may be substituted by C₁₋₈ alkyl group(s); R⁷ is selectedfrom the group consisting of: (1) a hydrogen atom, (2) a halogen atom,(3) a C₁₋₈ alkoxy group which may be substituted by one or more R^(7A),R^(7A): [1] a (C₁₋₈ alkyl)_(m7a)-amino group, [2] a hydroxy, [3] a 4- to10-membered heterocycloalkyl group which may be substituted by C₁₋₈alkyl group(s), m7a: 0˜2, (4) a C₁₋₈ alkylsulfonyl group, (5) a nitrogroup, and (6) a hydroxyl group; R⁸ is selected from the groupconsisting of: (1) a hydrogen atom, (2) a C₁₋₈ alkyl group which may besubstituted by one or more R^(8A), R^(8A): [1] a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(8A),[2] a (C₁₋₈ alkyl)_(m8a)-amino group which may be substituted by ahalogen atom, or [3] a hydroxy group, m8a: 0˜2, R^(8A): [1] a C₁₋₈ alkylgroup, [2] a C₁₋₈ alkylsulfonyl group, [3] a (C₁₋₈alkyl)_(m8b)-aminosulfonyl group, [4] an oxo group, [5] a C₁₋₈alkoxycarbonyl, or [6] a C₁₋₈ alkoxycarbonyl (C₀₋₈ alkyl) aminosulfonyl,m8b: 0˜2, (3) a C₂₋₈ alkenyl group, (4) a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(8B),R^(8B): <1> a C₁₋₈ alkyl group which may be substituted by one or moreR^(8B1), <2> a C₂₋₈ alkeynyl group, <3> a C₂₋₈ alkynyl group, <4> a C₃₋₈cycloalkyl group which may be substituted by [1] cyano group(s) or [2]C₁₋₈ alkyl group(s), <5> a 4- to 10-membered heterocycloalkyl groupwhich may be substituted by one or more R^(8B2), <6> a C₁₋₈ alkoxy groupwhich may be substituted by substituent(s) selected from the groupconsisting of [1] a C₁₋₈ alkoxy group and [2] a C₃₋₈ cycloalkyl group,<7> a C₁₋₈ alkoxycarbonyl group, <8> a C₁₋₈ alkylsulfonyl group, <9> a5- to 14-membered heteroarylsulfonyl group, <10> an oxo group, <11> acyano group, <12> a C₁₋₈ alkanoyl group which may be substituted by oneor more R^(8B3), <13> a C₃₋₈ cycloalkylcarbonyl group, <14> a (C₁₋₈alkyl)_(m8c)-aminosulfonyl group, <15> a C₁₋₈ alkylsulfonyl (C₀₋₈ alkyl)amino group, <16> a (C₁₋₈ alkyl)_(m8d)-amino group which may besubstituted by one or more R^(8B4), <17> a hydroxy group, <18> a (C₁₋₈alkyl)_(m8e)-aminocarbonyl group, or <19> a C₁₋₈ alkoxycarbonyl (C₀₋₈alkyl) amino group m8c: 0˜2 m8d: 0˜2 m8e: 0˜2 R^(8B1): [1] a C₃₋₈cycloalkyl group, [2] a hydroxy group, or [3] a C₁₋₈ alkoxy group(s),R^(8B2): [1] a halogen atom, [2] a C₁₋₈ alkyl group, [3] an oxo group,[4] a hydroxy group, or [5] a deuterium atom, R^(8B3): a (C₁₋₈alkyl)_(m8f)-amino group, m8f: 0˜2, R^(8B4): [1] a C₃₋₈ cycloalkylgroup, or [2] a hydroxy group, (5) a 5- to 14-membered heteroaryl groupwhich may be substituted by a C₁₋₈ alkyl group, (6) a (C₁₋₈alkyl)_(m8g)-aminocarbonyl group which may be substituted by one or moreR^(8C), m8g: 0˜2, R^(8C): [1] a hydroxy group, [2] a (C₁₋₈alkyl)_(m8h)-amino group which may be substituted by substituent(s)selected from the group consisting of <1> a (C₁₋₈alkyl)_(m8i)-aminosulfonyl group, <2> a C₁₋₈ alkylsulfonyl group, <3> aC₁₋₈ alkoxycarbonyl group and <4> a C₁₋₈ alkoxycarbonyl(C₀₋₈ alkyl)aminosulfonyl group, [3] a C₁₋₈ alkylsulfonyl group, or [4] a C₁₋₈alkoxy group which may be substituted by a hydroxy group, m8h: 0˜2, m8i:0˜2, (7) a 4- to 10-membered heterocycloalkyl (C₀₋₈ alkyl) aminocarbonylgroup which may be substituted by oxo group(s), (8) a 4- to 10-memberednitrogen-containing heterocycloalkylcarbonyl group which may besubstituted by one or more R^(8D), R^(8D): [1] a C₁₋₈ alkyl group whichmay be substituted by one or more R^(8D1), [2] a hydroxy group, [3] aC₁₋₈ alkylsulfonyl group, or [4] a C₁₋₈ alkoxycarbonyl group, R^(8D1):[1] a hydroxy group, or [2] a C₁₋₈ alkoxy group, (9) a hydroxycarbonylgroup, (10) a C₀₋₈ alkoxy (C₀₋₈ alkyl) aminocarbonyl group which may besubstituted by hydroxy group(s), (11) a halogen atom, (12) a (C₁₋₈alkyl)_(m8j)-amino group which may be substituted by one or more R^(8H),m8j: 0˜2, R^(8H): [1] a hydroxy group, or [2] a 4- to 10-memberedheterocycloalkyl group, (13) a hydroxyl group, (14) a C₁₋₈ alkoxy groupwhich may be substituted by one or more R^(8E), R^(8E): <1> a hydroxygroup, <2> halogen atom, <3> a hydroxycarbonyl group, <4> a C₁₋₈alkoxycarbonyl group, <5> a 4- to 10-membered nitrogen-containingheterocycloalkylcarbonyl group which may be substituted by one or moreR^(8E1), <6> a (C₁₋₈ alkyl)_(m8k1)-amino group which may be substitutedby one or more R^(8E2), m8k1: 0˜2, <7> a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(8E3),<8> a 5- to 14-membered heteroaryl group, <9> a (C₁₋₈alkyl)_(m8k2)-aminocarbonyl group which may be substituted by one ormore R^(8E6), m8k2: 0˜2, <10> a C₁₋₈ alkoxy group which may besubstituted by one or more R^(8E7), <11> a C₁₋₈ alkylthio group, <12> aC₁₋₈ alkylsulfinyl group, <13> a C₁₋₈ alkylsulfonyl group, R^(8E1): <1>a C₁₋₈ alkoxycarbonyl group, <2> a C₁₋₈ alkanoyl group, <3> a C₁₋₈alkylsulfonyl group, <4> a (C₁₋₈ alkyl)_(m8k3)-aminosulfonyl group,m8k3: 0˜2, or <5> a 4- to 10-membered heterocycloalkyl group, R^(8E2):<1> a hydroxy group, <2> a C₁₋₈ alkoxycarbonyl group which may besubstituted by halogen atom(s), <3> a C₃₋₈ cycloalkyl group which may besubstituted by C₁₋₈ alkyl group(s) which may be substituted by hydroxygroup(s), <4> a C₁₋₈ alkanoyl group which may be substituted bysubstituent(s) selected from the group consisting of [1] a (C₁₋₈alkyl)_(m8k4)-amino group and [2] a halogen atom(s), m8k4: 0˜2, <5> a(C₁₋₈ alkyl)_(m8k5)-aminocarbonyl group, m8k5: 0˜2, <6> a C₁₋₈alkylsulfonyl group, <7> a 4- to 10-membered nitrogen-containingheterocycloalkylsulfonyl group which may be substituted by C₁₋₈ alkylgroup(s), <8> a (C₁₋₈ alkyl)_(m8k6)-aminosulfonyl group which may besubstituted by C₁₋₈ alkoxycarbonyl group(s), m8k6: 0˜2, or R^(8E3): <1>a C₁₋₈ alkyl group which may be substituted by substituent(s) selectedfrom the group consisting of [1] a hydroxy group and [2] a C₁₋₈alkylcarbonyloxy group, <2> a C₁₋₈ alkylcarbonyloxy group, <3> a hydroxygroup, <4> a C₃₋₈ cycloalkyl group, <5> a C₁₋₈ alkoxy group, <6> a C₁₋₈alkoxycarbonyl group, <7> a C₁₋₈ alkylsulfonyl group, <8> a (C₁₋₈alkyl)_(m8k8)-aminocarbonyl group m8k8: 0˜2, <9> a C₁₋₈ alkanoyl groupwhich may be substituted by hydroxy group(s), <10> an oxo group, or <11>a 4- to 10-membered heterocycloalkyl group which may be substituted bysubstituent(s) selected from the group consisting of [1] a C₁₋₈ alkanoylgroup, [2] a C₁₋₈ alkoxycarbonyl group and [3] a C₁₋₈ alkylsulfonylgroup, R^(8E6): <1> a C₂₋₈ alkenylcarbonyloxy group, <2> a hydroxygroup, <3> a cyano group, <4> a (C₁₋₈ alkyl)_(m8k9)-amino group whichmay be substituted by hydroxy group(s) m8k9: 0˜2, <5> a C₁₋₈ alkoxygroup which may be substituted by hydroxy group(s), <6> a C₁₋₈alkylcarbonyloxy group, <7> a 4- to 10-membered heterocycloalkyl groupwhich may be substituted by C₁₋₈ alkyl group(s), or <8> a 5- to14-membered heteroaryl group, R^(8E7): <1> a hydroxy group, or <2> aC₁₋₈ alkoxy group which may be substituted by hydroxy group(s), (15) a4- to 10-membered heterocycloalkyloxy group which may be substituted byone or more R^(8F), R^(8F): <1> a C₁₋₈ alkyl group which may besubstituted by one or more R^(8F1), <2> a C₃₋₈ cycloalkyl group, <3> aC₁₋₈ alkanoyl group which may be substituted by halogen atom(s), <4> aC₁₋₈ alkylcarbonyloxy group, <5> a C₁₋₈ alkoxycarbonyl group, <6> a 4-to 10-membered heterocycloalkyl group which may be substituted by one ormore R^(8F2), <7> a C₁₋₈ alkyl sulfonyl group, <8> a hydroxy group, or[9] a C₆₋₁₀ aryl group, R^(8F1): [1] a hydroxy group, [2] a C₁₋₈ alkoxygroup, or [3] a halogen atom, R^(8F2): [1] a 4- to 10-memberedheterocycloalkyl group, [2] a C₁₋₈ alkoxycarbonyl group, or [3] a C₁₋₈alkylsulfonyl group, (16) a 5- to 14-membered heteroaryloxy group, (17)a 4- to 10-membered heterocycloalkylcarbonyloxy group, (18) a (C₁₋₈alkyl)_(m8l1)-aminosulfonyloxy group, m8l1: 0˜2, (19) a C₁₋₈ alkyl thiogroup which may be substituted by [1] (C₁₋₈ alkyl)_(m8l2)-aminogroup(s), [2] hydroxy group(s) or [3] hydroxycarbonyl group(s), m8l2:0˜2, (20) a C₁₋₈ alkylsulfonyl group which may be substituted by one ormore R^(8G), R^(8G): [1] a hydroxycarbonyl group, [2] a hydroxy group,or [3] a (C₁₋₈ alkyl)_(m8l3)-amino group, m8l3: 0˜2, (21) a 4- to10-membered nitrogen-containing heterocycloalkylsulfonyloxy group whichmay be substituted by C₁₋₈ alkyl group(s), (22) a C₂₋₈ alkenyloxy group,and (23) a C₁₋₈ alkylsulfonyloxy group which may be substituted byhalogen atom(s); R⁹ is selected from the group consisting of: (1) ahydrogen atom, (2) a C₁₋₈ alkyl group which may be substituted by one ormore R^(9A), R^(9A): [1] a C₃₋₈ cycloalkyl group, [2] a 4- to10-membered heterocycloalkyl group which may be substituted by one ormore R^(9A1), [3] a hydroxy group, [4] a C₁₋₈ alkoxy group, or [5] ahydroxycarbonyl group, R^(9A1): [1] a C₁₋₈ alkyl group, [2] a C₃₋₈cycloalkyl group, or [3] a 4- to 10-membered heterocycloalkyl group, (3)a C₂₋₈ alkenyl group which may be substituted by one or more R^(9B),R^(9B): [1] a (C₁₋₈ alkyl)_(m9a)-amino group, [2] a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more groupR^(9B1), R^(9B1): [1] a C₃₋₈ cycloalkyl group, or [2] a 4- to10-membered heterocycloalkyl group, m9a: 0˜2, (4) a C₂₋₈ alkynyl groupwhich may be substituted by one or more R^(9C), R^(9C): [1] a C₁₋₈alkoxy group, [2] a (C₁₋₈ alkyl)_(m9b)-amino group which may besubstituted by C₆₋₁₀ aryl group(s), [3] a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(9C1),[4] a C₃₋₈ cycloalkyl group, [5] a hydroxy group, [6] a hydroxycarbonylgroup, or [7] a C₁₋₈ alkyloxycarbonyl group, m9b: 0˜2, R^(9C1): [1] aC₃₋₈ cycloalkyl group, [2] a 4- to 10-membered heterocycloalkyl group,or [3] an oxo group, (5) a C₃₋₈ cycloalkyl group, (6) a 4- to10-membered heterocycloalkyl group which may be substituted by one ormore R^(9D), R^(9D): [1] a C₁₋₈ alkyl group which may be substituted by4- to 10-membered heterocycloalkyl group(s), [2] a C₃₋₈ cycloalkylgroup, [3] a 4- to 10-membered heterocycloalkyl group, or [4] a C₁₋₆alkylsulfonyl group, or [5] a C₁₋₈ alkoxycarbonyl group, (7) a C₆₋₁₀aryl group which may be substituted by one or more R^(9E), R^(9E): [1] ahalogen atom, [2] a hydroxy group, [3] a hydroxycarbonyl group, or [4] aC₁₋₈ alkyl group which may be substituted by hydroxy group(s), or [5] aC₁₋₈ alkoxy group, (8) a 5- to 14-membered heteroaryl group which may besubstituted by C₁₋₈ alkyl group(s), (9) a cyano group, (10) a C₁₋₈alkanoyl group, (11) a 4- to 10-membered nitrogen-containingheterocycloalkylcarbonyl group which may be substituted by C₁₋₈ alkylgroup(s), (12) a halogen atom, (13) a (C₁₋₈ alkyl)_(m9c)-amino groupwhich may be substituted by one or more R^(9F), m9c: 0˜2, (14) a C₁₋₈alkylcarbonyl(C₀₋₈ alkyl)amino group which may be substituted by (C₁₋₈alkyl)_(m9d)-amino group(s), m9d: 0˜2, (15) a C₁₋₈ alkylsulfonyl(C₀₋₈alkyl)amino group, (16) a (C₁₋₈ alkyl)_(m9e)-aminosulfonyl(C₀₋₈alkyl)amino group, m9e: 0˜2, (17) a nitro group, (18) a hydroxy group,(19) a C₁₋₈ alkoxy group which may be substituted by one or more R^(9G),R^(9G): [1] a hydroxy group, [2] a hydroxycarbonyl group, [3] a C₆₋₁₀aryl group which may be substituted by C₁₋₈ alkoxy group(s), [4] a (C₁₋₈alkyl)_(m9g1)-amino group, [5] a C₁₋₈ alkoxy group which may besubstituted by one or more R^(9G1), [6] a 5- to 14-membered heteroarylgroup, or [7] a 4- to 10-membered heterocycloalkyloxy group which may besubstituted by C₁₋₈ alkyl group(s), m9g1: 0˜2, R^(9G1): [1] a C₁₋₈alkoxy group, or [2] a hydroxycarbonyl group, (20) a 4- to 10-memberedheterocycloalkyloxy group which may be substituted by [1] 4- to10-membered heterocycloalkyl group(s), or [2] C₁₋₈ alkoxycarbonylgroup(s), (21) a C₁₋₈ alkylsulfonyloxy group which may be substituted byhalogen atom(s), (22) a C₁₋₈ alkylthio group which may be substituted by(C₁₋₈ alkyl)_(m9f)-amino group(s), m9f: 0˜2, (23) a C₁₋₈ alkylsulfonylgroup which may be substituted by (C₁₋₈ alkyl)_(m9g)-amino group(s),m9g: 0˜2, (24) a (C₁₋₈ alkyl)_(m9h)-aminosulfonyl group, m9h: 0˜2, (25)a 4- to 10-membered nitrogen-containing heterocycloalkylsulfonyl groupwhich may be substituted by C₁₋₈ alkyl group(s), and (26) ahydroxycarbonyl group.
 2. The compound according to claim 1, or a saltor solvate thereof, wherein R³ is a cyano group or a halogen atom. 3.The compound according to claim 1, or a salt or solvate thereof, whereinA⁵ is NR⁵ and R⁵ is a hydrogen atom.
 4. The compound according to claim1, or a salt or solvate thereof, wherein all of the A¹, A², A³, A⁴, A⁷,A⁸, A⁹ and A¹⁰ are a carbon atom.
 5. The compound according to claim 1,or a salt or solvate thereof, wherein: A¹, A², A³, A⁴, A⁷, A⁸, A⁹ andA¹⁰ all represent C, or any one of A², A³, A⁴, A⁷, A⁸ and A⁹ representsN (with the proviso that, when it represents N, no substituent groupexists therefor) and the remainings represent C; A⁵ is selected fromNR⁵, O and S; R¹ represents [1] a hydrogen atom, [2] a cyano group, or[3] a halogen atom; R² is selected from the group consisting of: (1) ahydrogen atom, (2) a C₁₋₈ alkyl group, (3) a cyano group, (4) a halogenatom, and (5) a (C₁₋₈ alkyl)_(m2)-amino group which may be substitutedby C₁₋₈ alkylsulfonyl group(s), m2: 0˜2; R³ is selected from the groupconsisting of: (1) a hydrogen atom, (2) a C₁₋₈ alkyl group which may besubstituted by halogen atom(s), (3) a cyano group, (4) a (C₁₋₈alkyl)_(m3a)-aminocarbonyl group which may be substituted by one or moreR^(3A), R^(3A): [1] a C₆₋₁₀ aryl group, [2] a C₁₋₈ alkoxy group, [3] a5- to 14-membered heteroaryl group, or [4] a C₆₋₁₀ aryl sulfonyl group,m3a: 0˜2, (5) a hydroxycarbonyl group, (6) a C₁₋₈ alkoxycarbonyl groupwhich may be substituted by hydroxy group(s), (7) a halogen atom, (8) a(C₁₋₈ alkyl)_(m3b)-amino group which may be substituted by C₆₋₁₀ arylgroup(s), m3b: 0˜2, (9) a C₁₋₈ alkylcarbonyl (C₀₋₈ alkyl) amino groupwhich may be substituted by [1]C₆₋₁₀ aryl group(s) or [2] C₆₋₁₀ aryloxygroup(s), (10) a C₆₋₁₀ arylcarbonyl (C₀₋₈ alkyl) amino group which maybe substituted by C₁₋₈ alkyl group(s) which may be substituted byhalogen atom(s), (11) a nitro group, (12) a hydroxy group, (13) a C₁₋₈alkoxy group which may be substituted by one or more R^(3B), R^(3B): [1]a hydroxy group, [2] a C₁₋₈ alkoxy group, [3] a C₆₋₁₀ aryl (C₀₋₈ alkyl)aminocarbonyl group, [4] a (C₁₋₈ alkyl)_(m3d)-amino group, or [5] ahalogen atom, m3d: 0˜2, (14) a 4- to 10-membered heterocycloalkyloxygroup, (15) a 5- to 14-membered heteroaryloxy group, (16) a (C₁₋₈alkyl)_(m3e)-aminocarbonyloxy group which may be substituted by C₆₋₁₀aryl group(s), m3e: 0˜2, (17) a 4- to 10-membered nitrogen-containingheterocycloalkylcarbonyl group, (18) a C₁₋₈ alkylthio group, (19) a 5-to 14-membered heteroaryl group which may be substituted by C₁₋₈ alkylgroup(s) which may be substituted by C₁₋₈ alkoxy group(s), (20) a C₁₋₈alkoxycarbonyl (C₀₋₈ alkyl) amino group which may be substituted by C₁₋₈alkoxy group(s), (21) a C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl) amino groupwhich may be substituted by C₁₋₈ alkyl group(s) which may be substitutedby halogen atom(s), (22) a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈alkyl) amino group which may be substituted by C₁₋₈ alkoxy group(s),(23) a C₃₋₈ cycloalkyl (C₀₋₈ alkyl) aminocarbonyloxy group, and (24) aC₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyloxy group which may be substitutedby substituent(s) selected from the group consisting of [1] a C₁₋₈ alkylgroup and [2] a C₁₋₈ alkoxy group; R⁴ is selected from the groupconsisting of: (1) a hydrogen atom, (2) a C₁₋₈ alkyl group which may besubstituted by halogen atom(s), (3) a C₃₋₈ cycloalkyl group, (4) a cyanogroup, (5) an aminocarbonyl group, (6) a hydroxycarbonyl group, (7) ahalogen atom, (8) a (C₁₋₈ alkyl)_(m4b)-amino group, m4b: 0˜2, (9) ahydroxy group, and (10) a C₁₋₈ alkoxy group which may be substituted byhydroxy group(s); R⁵ is selected from the group consisting of: (1) ahydrogen atom, (2) a C₁₋₈ alkyl group which may be substituted by one ormore R^(5A), R^(5A): [1] a hydroxycarbonyl group, [2] a C₁₋₈alkoxycarbonyl group, [3] a hydroxy group, [4] a C₁₋₈ alkoxy group, [5]a (C₁₋₈ alkyl)_(m5)-amino group, or [6] a C₁₋₈ alkylthio group, m5: 0˜2,and (3) a C₁₋₈ alkylsulfonyl group; R⁶ and R^(6′) are eachindependently: (1) a C₁₋₈ alkyl group, or R⁶ and R^(6′) are takentogether with the carbon atoms to which they are bound to form, (2) aC₃₋₈ cycloalkyl group, or (3) a 4- to 10-membered heterocycloalkylgroup; R⁷ is selected from the group consisting of: (1) a hydrogen atom,(2) a halogen atom, and (3) a C₁₋₈ alkoxy group which may be substitutedby one or more R^(7A), R^(7A): [1] a (C₁₋₈ alkyl)_(m7a)-amino group, or[2] a hydroxy group, m7a: 0-2; R⁸ is selected from the group consistingof: (1) a hydrogen atom, (2) a C₁₋₈ alkyl group which may be substitutedby one or more R^(8A), R^(8A): [1] a 4- to 10-membered heterocycloalkylgroup which may be substituted by one or more R^(8A1), [2] a (C₁₋₈alkyl)_(m8a)-amino group which may be substituted by a halogen atom, or[3] a hydroxy group, m8a: 0-2, R^(8A1): [1] a C₁₋₈ alkyl group, [2] aC₁₋₈ alkylsulfonyl group, [3] a (C₁₋₈ alkyl)_(m8b-) aminosulfonyl group,or [4] an oxo group, m8b: 0˜2, (3) a C₂₋₈ alkenyl group, (4) a 4- to10-membered heterocycloalkyl group which may be substituted by one ormore R^(8B), R^(8B): <1> a C₁₋₈ alkyl group which may be substituted byone or more R^(8B1), <2> a C₂₋₈ alkynyl group, <3> a C₃₋₈ cycloalkylgroup which may be substituted by [1] cyano group(s) or [2] C₁₋₈ alkylgroup(s), <4> a 4- to 10-membered heterocycloalkyl group which may besubstituted by one or more R^(8B2), <5> a C₁₋₈ alkoxy group which may besubstituted by substituent(s) selected from the group consisting of [1]a C₁₋₈ alkoxy group and [2] a C₃₋₈ cycloalkyl group, <6> a C₁₋₈alkylsulfonyl group, <7> an oxo group, <8> a cyano group, <9> a C₁₋₈alkanoyl group which may be substituted by one or more R^(8B3), <10> aC₃₋₈ cycloalkylcarbonyl group, <11> a (C₁₋₈ alkyl)_(m8c)-aminosulfonylgroup, <12> a C₁₋₈ alkylsulfonyl (C₀₋₈ alkyl) amino group, <13> a (C₁₋₈alkyl)_(m8d)-amino group which may be substituted by one or moreR^(8B4), <14> a hydroxy group, or <15> a (C₁₋₈alkyl)_(m8e)-aminocarbonyl group, m8c: 0˜2, m8d: 0˜2, m8e: 0˜2, R^(8B1):[1] a C₃₋₈ cycloalkyl group, [2] a hydroxy group, or [3] C₁₋₈ alkoxygroup which may be substituted by C₁₋₈ alkoxy group(s), R^(8B2): [1] ahalogen atom, [2] a C₁₋₈ alkyl group, [3] an oxo group, or [4] a hydroxygroup, R^(8B3): a (C₁₋₈ alkyl)_(m8f)-amino group, m8f: 0˜2, R^(8B4): [1]a C₃₋₈ cycloalkyl group, or [2] a hydroxy group, (5) a 5- to 14-memberedheteroaryl group which may be substituted by a C₁₋₈ alkyl group, (6) a(C₁₋₈ alkyl)_(m8g)-aminocarbonyl group which may be substituted by oneor more R^(8C), m8g: 0˜2, R^(8C): [1] a hydroxy group, [2] a (C₁₋₈alkyl)_(m8h)-amino group which may be substituted by substituent(s)selected from the group consisting of <1> a (C₁₋₈alkyl)_(m8i)-aminosulfonyl group and <2> a C₁₋₈ alkylsulfonyl group, or[3] a C₁₋₈ alkylsulfonyl group, m8h: 0˜2, m8i: 0˜2, (7) a 4- to10-membered heterocycloalkyl (C₀₋₈ alkyl) aminocarbonyl group which maybe substituted by oxo group(s), (8) a 4- to 10-memberednitrogen-containing heterocycloalkylcarbonyl group which may besubstituted by one or more R^(8D), R^(8D): [1] a C₁₋₈ alkyl group whichmay be substituted by one or more R^(8D1), [2] a hydroxy group, or [3] aC₁₋₈ alkylsulfonyl group, R^(8D1): [1] a hydroxy group, or [2] a C₁₋₈alkoxy group, (9) a hydroxycarbonyl group, (10) a C₀₋₈ alkoxy (C₀₋₈alkyl) aminocarbonyl group which may be substituted by hydroxy group(s),(11) a halogen atom, (12) a (C₁₋₈ alkyl)_(m8j)-amino group which may besubstituted by 4- to 10-membered heterocycloalkyl group(s), m8j: 0˜2,(13) a hydroxyl group, (14) a C₁₋₈ alkoxy group which may be substitutedby one or more R^(E), R^(8E): <1> a hydroxy group, <2> a C₁₋₈alkoxycarbonyl group, <3> a 4- to 10-membered nitrogen-containingheterocycloalkylcarbonyl group which may be substituted by one or moreR^(8E1), <4> a (C₁₋₈ alkyl)_(m8k1)-amino group which may be substitutedby one or more R^(8E2), m8k1: 0˜2, <5> a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(8E3),<6> a 5- to 14-membered heteroaryl group, <7> a (C₁₋₈alkyl)_(m8k2)-aminocarbonyl group which may be substituted by one ormore R^(8E6) m8k2: 0˜2, <8> a C₁₋₈ alkoxy group which may be substitutedby one or more R^(8E7), <9> a C₁₋₈ alkylthio group, <10> a C₁₋₈alkylsulfinyl group, or <11> a C₁₋₈ alkylsulfonyl group, R^(8E1): <1> aC₁₋₈ alkoxycarbonyl group, <2> a C₁₋₈ alkanoyl group, <3> a C₁₋₈alkylsulfonyl group, <4> a (C₁₋₈ alkyl)_(m8k3)-aminosulfonyl group m8k3:0˜2, or <5> a 4- to 10-membered heterocycloalkyl group, R^(8E2): <1> ahydroxy group, <2> a C₁₋₈ alkoxycarbonyl group, <3> a C₃₋₈ cycloalkylgroup which may be substituted by C₁₋₈ alkyl group(s) which may besubstituted by hydroxy group(s), <4> a C₁₋₈ alkanoyl group which may besubstituted by substituent(s) selected from the group consisting of [1]a (C₁₋₈ alkyl)_(m8k4)-amino group and [2] a halogen atom, m8k4: 0˜2, <5>a (C₁₋₈ alkyl)_(m8k5)-aminocarbonyl group, m8k5: 0˜2, <6> a C₁₋₈alkylsulfonyl group, <7> a 4- to 10-membered nitrogen-containingheterocycloalkylsulfonyl group which may be substituted by C₁₋₈ alkylgroup(s), <8> a (C₁₋₈ alkyl)_(m8k6)-aminosulfonyl group, m8k6: 0˜2, orR^(8E3): <1> a C₁₋₈ alkyl group which may be substituted bysubstituent(s) selected from the group consisting of [1] a hydroxy groupand [2] a C₁₋₈ alkylcarbonyloxy group, <2> a hydroxy group, <3> a C₃₋₈cycloalkyl group, <4> a C₁₋₈ alkylsulfonyl group, <5> a (C₁₋₈alkyl)_(m8k8)-aminocarbonyl group, m8k8: 0˜2, <6> a C₁₋₈ alkanoyl groupwhich may be substituted by hydroxy group(s), <7> an oxo group, or <8> a4- to 10-membered heterocycloalkyl group which may be substituted bysubstituent(s) selected from the group consisting of [1] a C₁₋₈ alkanoylgroup, and [2] a C₁₋₈ alkylsulfonyl group, R^(8E6): <1> a C₂₋₈alkenylcarbonyloxy group, <2> a hydroxy group, <3> a cyano group, <4> a(C₁₋₈ alkyl)_(m8k9)-amino group which may be substituted by hydroxygroup(s), m8k9: 0˜2, <5> a C₁₋₈ alkoxy group which may be substituted byhydroxy group(s), <6> a 4- to 10-membered heterocycloalkyl group whichmay be substituted by C₁₋₈ alkyl group(s), or <7> a 5- to 14-memberedheteroaryl group, R^(8E7): <1> a hydroxy group, or <2> a C₁₋₈ alkoxygroup which may be substituted by hydroxy group(s), (15) a 4- to10-membered heterocycloalkyloxy group which may be substituted by one ormore R^(8F): R^(8F): <1> a C₁₋₈ alkyl group which may be substituted byone or more R^(8F1), <2> a C₃₋₈ cycloalkyl group, <3> a C₁₋₈ alkanoylgroup which may be substituted by halogen atom(s), <4> a C₁₋₈alkoxycarbonyl group, <5> a 4- to 10-membered heterocycloalkyl groupwhich may be substituted by one or more R^(8F2), <6> a C₁₋₈ alkylsulfonyl group, or <7> a hydroxy group, R^(8F1): [1] a hydroxy group,[2] a C₁₋₈ alkoxy group, or [3] a halogen atom, R^(8F2): [1] a 4- to10-membered heterocycloalkyl group, [2] a C₁₋₈ alkoxycarbonyl group, or[3] a C₁₋₈ alkylsulfonyl group, (16) a 5- to 14-membered heteroaryloxygroup, (17) a (C₁₋₈ alkyl)_(m811)-aminosulfonyloxy group, m8l1: 0˜2,(18) a C₁₋₈ alkylthio group which may be substituted by (C₁₋₈alkyl)_(m8l2)-amino group(s), m8l2: 0˜2, (19) a C₁₋₈ alkylsulfonyl groupwhich may be substituted by one or more R^(8G), R^(8G): [1] ahydroxycarbonyl group, [2] a hydroxy group, or [3] a (C₁₋₈alkyl)_(m8l3)-amino group, m8l3: 0˜2, (20) a C₂₋₈ alkenyloxy group, and(21) a C₁₋₈ alkylsulfonyloxy group which may be substituted by halogenatom(s); R⁹ is selected from the group consisting of: (1) a hydrogenatom, (2) a C₁₋₈ alkyl group which may be substituted by one or moreR^(9A), R^(9A): [1] a C₃₋₈ cycloalkyl group, [2] a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(9A1),[3] a hydroxy group, or [4] a C₁₋₈ alkoxy group, R^(9A1): [1] a C₁₋₈alkyl group, [2] a C₃₋₈ cycloalkyl group, or [3] a 4- to 10-memberedheterocycloalkyl group, (3) a C₂₋₈ alkenyl group, (4) a C₂₋₈ alkynylgroup which may be substituted by one or more R^(9C), R^(9C): [1] a C₁₋₈alkoxy group, [2] a (C₁₋₈ alkyl)_(m9b)-amino group which may besubstituted by C₆₋₁₀ aryl group(s), [3] a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(9C1),[4] a C₃₋₈ cycloalkyl group, [5] a hydroxy group, or [6] ahydroxycarbonyl group, m9b: 0˜2, R^(9C1): [1] a C₃₋₈ cycloalkyl group,[2] a 4- to 10-membered heterocycloalkyl group, or [3] an oxo group, (5)a C₃₋₈ cycloalkyl group, (6) a 4- to 10-membered heterocycloalkyl groupwhich may be substituted by one or more R^(9D), R^(9D): [1] a C₁₋₈ alkylgroup which may be substituted by 4- to 10-membered heterocycloalkylgroup(s), [2] a C₃₋₈ cycloalkyl group, [3] a 4- to 10-memberedheterocycloalkyl group, or [4] a C₁₋₆ alkylsulfonyl group, (7) a C₆₋₁₀aryl group which may be substituted by one or more R^(9E), R^(9E): [1] ahalogen atom, [2] a hydroxy group, [3] a hydroxycarbonyl group, or [4] aC₁₋₈ alkyl group which may be substituted by hydroxy group(s), (8) a 5-to 14-membered heteroaryl group which may be substituted by C₁₋₈ alkylgroup(s), (9) a cyano group, (10) a C₁₋₈ alkanoyl group, (11) a 4- to10-membered nitrogen-containing heterocycloalkylcarbonyl group which maybe substituted by C₁₋₈ alkyl group(s), (12) a halogen atom, (13) a (C₁₋₈alkyl)_(m9c)-amino group, m9c: 0˜2, (14) a C₁₋₈ alkylcarbonyl(C₀₋₈alkyl)amino group which may be substituted by (C₁₋₈ alkyl)_(m9d)-aminogroup(s), m9d: 0˜2, (15) a C₁₋₈ alkylsulfonyl(C₀₋₈ alkyl)amino group,(16) a (C₁₋₈ alkyl)_(m9e)-aminosulfonyl(C₀₋₈ alkyl)amino group, m9e:0˜2, (17) a nitro group, (18) a hydroxy group, (19) a C₁₋₈ alkoxy groupwhich may be substituted by one or more R^(9G), R^(9G): [1] a hydroxygroup, [2] a hydroxycarbonyl group, [3] a C₆₋₁₀ aryl group which may besubstituted by C₁₋₈ alkoxy group(s), [4] a (C₁₋₈ alkyl)_(m9g1)-aminogroup, [5] a C₁₋₈ alkoxy group which may be substituted by one or moreR^(9G1), or [6] a 5- to 14-membered heteroaryl group, m9g1: 0˜2,R^(9G1): [1] a C₁₋₈ alkoxy group, or [2] a hydroxycarbonyl group, (20) a4- to 10-membered heterocycloalkyloxy group which may be substituted by4- to 10-membered heterocycloalkyl group(s), (21) a C₁₋₈ alkylthio groupwhich may be substituted by (C₁₋₈ alkyl)_(m9f)-amino group(s), m9f: 0˜2,(22) a C₁₋₈ alkylsulfonyl group which may be substituted by (C₁₋₈alkyl)_(m9g)-amino group(s), m9g: 0˜2, (23) a (C₁₋₈alkyl)_(m9h)-aminosulfonyl group, m9h: 0˜2, and (24) a 4- to 10-memberednitrogen-containing heterocycloalkylsulfonyl group which may besubstituted by C₁₋₈ alkyl group(s); R¹⁰ represents [1] a hydrogen atom,or [2] a 4- to 10-membered heterocycloalkyl group which may besubstituted by 4- to 10-membered heterocycloalkyl group(s)].
 6. Acompound or salt or solvate thereof, which said compound is selectedfrom the group consisting of:9-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-1-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(1-isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(2-tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;and9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.7. A medicament comprising as an active ingredient the compoundaccording to claim 1, or a salt or solvate thereof.
 8. An ALK inhibitorcomprising as an active ingredient the compound according to claim 1, ora salt or solvate thereof.
 9. A pharmaceutical for the prophylaxis ortreatment of cancer, cancer metastasis, depression or cognitive functiondisorder, comprising as an active ingredient the compound according toclaim 1, or a salt or solvate thereof.
 10. A pharmaceutical compositioncomprising the compound according to claim 1, or a salt or solvatethereof and a pharmaceutically acceptable carrier(s).
 11. A method oftreating or preventing cancer, cancer metastasis, depression orcognitive function disorder in a subject in need thereof comprisingadministering an effective amount of a pharmaceutical for the treatmentof cancer, cancer metastasis, depression or cognitive function disorder,comprising as an active ingredient a compound represented by Formula(I):

wherein, A⁵ is selected from NR⁵, O and S; A⁴, A⁷, and A⁹ represent CR⁴,CR⁷, and CR⁹ respectively, or wherein A⁴ is N and A⁷ and A⁹ representCR⁷ and CR⁹ respectively; R¹ and R¹⁰ each independently represent [1] ahydrogen atom, [2] a cyano group, [3] a halogen atom or [4] a 4- to10-membered heterocycloalkyl group which may be substituted by 4- to10-membered heterocycloalkyl group(s); R² is selected from the groupconsisting of: (1) a hydrogen atom, (2) a C₁₋₈ alkyl group, (3) a C₂₋₈alkenyl group, (4) a C₂₋₈ alkynyl group, (5) a cyano group, (6) ahalogen atom, (7) a (C₁₋₈ alkyl)_(m2)-amino group which may besubstituted by C₁₋₈ alkylsulfonyl group(s), m2: 0˜2, and (8) a nitrogroup; R³ is selected from the group consisting of: (1) a hydrogen atom,(2) a C₁₋₈ alkyl group which may be substituted by [1] halogen atom(s),[2]hydroxy group(s) or [3] C₁₋₈ alkoxy group(s), (3) a C₆₋₁₀ aryl group,(4) a cyano group, (5) a C₁₋₈ alkanoyl group which may be substituted byC₆₋₁₀ aryl group(s), (6) a (C₁₋₈ alkyl)_(m3a)-aminocarbonyl group whichmay be substituted by one or more R^(3A), R^(3A): [1] a C₆₋₁₀ arylgroup, [2] a C₁₋₈ alkoxy group, [3] a 5- to 14-membered heteroarylgroup, or [4] a C₆₋₁₀ arylsulfonyl group, m3a: 0˜2, (7) ahydroxycarbonyl group, (8) a C₁₋₈ alkoxycarbonyl group which may besubstituted by [1] hydroxy group(s) or [2] C₁₋₈ alkoxy group(s), (9) ahalogen atom, (10) a (C₁₋₈ alkyl)_(m3b)-amino group which may besubstituted by C₆₋₁₀ aryl group(s), m3b: 0˜2, (11) a C₁₋₈ alkylcarbonyl(C₀₋₈ alkyl) amino group which may be substituted by [1]C₆₋₁₀ arylgroup(s) or [2] C₆₋₁₀ aryloxy group(s), (12) a C₆₋₁₀ arylcarbonyl (C₀₋₈alkyl) amino group which may be substituted by C₁₋₈ alkyl group(s) whichmay be substituted by halogen atom(s), (13) a (C₁₋₈alkyl)_(m3c)-aminocarbonyl (C₀₋₈ alkyl) amino group which may besubstituted by C₆₋₁₀ aryl group(s), m3c: 0˜2, (14) a nitro group, (15) ahydroxy group, (16) a C₁₋₈ alkoxy group which may be substituted by oneor more R^(3B), R^(3B): [1] a hydroxy group, [2] a C₁₋₈ alkoxy group,[3] a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl group, [4] a (C₁₋₈alkyl)_(m3d)-amino group, or [5] a halogen atom, m3d: 0˜2, (17) a 4- to10-membered heterocycloalkyloxy group, (18) a 5- to 14-memberedheteroaryloxy group, (19) a (C₁₋₈ alkyl)_(m3e)-aminocarbonyloxy groupwhich may be substituted by C₆₋₁₀ aryl group(s) m3e: 0˜2, (20) a 4- to10-membered nitrogen-containing heterocycloalkylcarbonyl group, (21) aC₁₋₈ alkylsulfonyloxy group which may be substituted by halogen atom(s),(22) a C₁₋₈ alkylthio group, (23) a C₁₋₈ alkylsulfonyl group which maybe substituted by C₆₋₁₀ aryl group(s), (24) a 5- to 14-memberedheteroaryl group which may be substituted by C₁₋₈ alkyl group(s) whichmay be substituted by C₁₋₈ alkoxy group(s), (25) a C₁₋₈ alkoxycarbonyl(C₀₋₈ alkyl) amino group which may be substituted by C₁₋₈ alkoxygroup(s), (26) a C₆₋₁₀ aryloxycarbonyl (C₀₋₈ alkyl) amino group whichmay be substituted by C₁₋₈ alkyl group(s) which may be substituted byhalogen atom(s), (27) a C₆₋₁₀ aryl (C₀₋₈ alkyl) aminocarbonyl (C₀₋₈alkyl) amino group which may be substituted by one or more R^(3C),R^(3C): [1] a C₁₋₈ alkyl group which may be substituted by halogenatom(s), or [2] a C₁₋₈ alkoxy group, (28) a C₃₋₈ cycloalkyl (C₀₋₈ alkyl)aminocarbonyloxy group, and (29) a C₆₋₁₀ aryl (C₀₋₈ alkyl)aminocarbonyloxy group which may be substituted by substituent(s)selected from the group consisting of [1] a C₁₋₈ alkyl group and [2] aC₁₋₈ alkoxy group; R⁴ is selected from the group consisting of: (1) ahydrogen atom, (2) a C₁₋₈ alkyl group which may be substituted byhalogen atom(s), (3) a C₂₋₈ alkenyl group, (4) a C₂₋₈ alkynyl group, (5)a C₃₋₈ cycloalkyl group, (6) a cyano group, (7) an aminocarbonyl group,(8) a (C₁₋₈ alkyl)_(m4a)-aminocarbonyl group, m4a: 1˜2, (9) ahydroxycarbonyl group, (10) a C₁₋₈ alkoxycarbonyl group, (11) a halogenatom, (12) a (C₁₋₈ alkyl)_(m4b)-amino group, m4b: 0˜2, (13) a hydroxygroup, and (14) a C₁₋₈ alkoxy group which may be substituted by hydroxygroup(s); R⁵ is selected from the group consisting of: (1) a hydrogenatom, (2) a C₁₋₈ alkyl group which may be substituted by one or moreR^(5A), R^(5A): [1] a hydroxycarbonyl group, [2] a C₁₋₈ alkoxycarbonylgroup, [3] a hydroxy group, [4] a C₁₋₈ alkoxy group, [5] a (C₁₋₈alkyl)_(m5)-amino group, [6] a C₆₋₁₀ aryl group, or [7] a C₁₋₈ alkylthiogroup, m5: 0˜2, (3) a C₂₋₈ alkenyl group, (4) a C₂₋₈ alkynyl group, (5)a C₃₋₈ cycloalkyl group, and (6) a C₁₋₈ alkylsulfonyl group; R⁶ andR^(6′) are each independently selected from the group consisting of: (1)a C₁₋₈ alkyl group which may be substituted by halogen atom(s), (2) aC₂₋₈ alkenyl group, and (3) a C₂₋₈ alkynyl group; or R⁶ and R^(6′) aretaken together with the carbon atoms to which they are bound to form:(4) a C₃₋₈ cycloalkyl group, or (5) a 4- to 10-membered heterocycloalkylgroup which may be substituted by C₁₋₈ alkyl C₆₋₁₀ aryl sulfonylgroup(s) which may be substituted by C₁₋₈ alkyl group(s); R⁷ is selectedfrom the group consisting of: (1) a hydrogen atom, (2) a halogen atom,(3) a C₁₋₈ alkoxy group which may be substituted by one or more R^(7A),R^(7A): [1] a (C₁₋₈ alkyl)_(m7a)-amino group, [2] a hydroxy, [3] a 4- to10-membered heterocycloalkyl group which may be substituted by C₁₋₈alkyl group(s), m7a: 0˜2, (4) a C₁₋₈ alkylsulfonyl group, (5) a nitrogroup, and (6) a hydroxyl group; R⁸ is selected from the groupconsisting of: (1) a hydrogen atom, (2) a C₁₋₈ alkyl group which may besubstituted by one or more RA, R^(8A): [1] a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(8A1),[2] a (C₁₋₈ alkyl)_(m8a)-amino group which may be substituted by ahalogen atom, or [3] a hydroxy group, m8a: 0-2, R^(8A1): [1] a C₁₋₈alkyl group, [2] a C₁₋₈ alkylsulfonyl group, [3] a (C₁₋₈alkyl)_(m8b)-aminosulfonyl group, [4] an oxo group, [5] a C₁₋₈alkoxycarbonyl, or [6] a C₁₋₈ alkoxycarbonyl (C₀₋₈ alkyl) aminosulfonyl,m8b: 0˜2, (3) a C₂₋₈ alkenyl group, (4) a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(8B),R^(8B): <1> a C₁₋₈ alkyl group which may be substituted by one or moreR^(8B1), <2> a C₂₋₈ alkeynyl group, <3> a C₂₋₈ alkynyl group, <4> a C₃₋₈cycloalkyl group which may be substituted by [1] cyano group(s) or [2]C₁₋₈ alkyl group(s), <5> a 4- to 10-membered heterocycloalkyl groupwhich may be substituted by one or more R^(8B2), <6> a C₁₋₈ alkoxy groupwhich may be substituted by substituent(s) selected from the groupconsisting of [1] a C₁₋₈ alkoxy group and [2] a C₃₋₈ cycloalkyl group,<7> a C₁₋₈ alkoxycarbonyl group, <8> a C₁₋₈ alkylsulfonyl group, <9> a5- to 14-membered heteroarylsulfonyl group, <10> an oxo group, <11> acyano group, <12> a C₁₋₈ alkanoyl group which may be substituted by oneor more R^(8B3), <13> a C₃₋₈ cycloalkylcarbonyl group, <14> a (C₁₋₈alkyl)_(m8c)-aminosulfonyl group, <15> a C₁₋₈ alkylsulfonyl (C₀₋₈ alkyl)amino group, <16> a (C₁₋₈ alkyl)_(m8d)-amino group which may besubstituted by one or more R^(8B4), <17> a hydroxy group, <18> a (C₁₋₈alkyl)_(m8e)-aminocarbonyl group, or <19> a C₁₋₈ alkoxycarbonyl (C₀₋₈alkyl) amino group m8c: 0˜2 m8d: 0˜2 m8e: 0˜2 R^(8B1): [1] a C₃₋₈cycloalkyl group, [2] a hydroxy group, or [3] a C₁₋₈ alkoxy group(s),R^(8B2): [1] a halogen atom, [2] a C₁₋₈ alkyl group, [3] an oxo group,[4] a hydroxy group, or [5] a deuterium atom, R^(8B3): a (C₁₋₈alkyl)_(m8f)-amino group, m8f: 0˜2, R^(8B4): [1] a C₃₋₈ cycloalkylgroup, or [2] a hydroxy group, (5) a 5- to 14-membered heteroaryl groupwhich may be substituted by a C₁₋₈ alkyl group, (6) a (C₁₋₈alkyl)_(m8g)-aminocarbonyl group which may be substituted by one or moreR^(8C), m8g: 0˜2, R^(8C): [1] a hydroxy group, [2] a (C₁₋₈alkyl)_(m8h)-amino group which may be substituted by substituent(s)selected from the group consisting of <1> a (C₁₋₈alkyl)_(m8i)-aminosulfonyl group, <2> a C₁₋₈ alkylsulfonyl group, <3> aC₁₋₈ alkoxycarbonyl group and <4> a C₁₋₈ alkoxycarbonyl(C₀₋₈ alkyl)aminosulfonyl group, [3] a C₁₋₈ alkylsulfonyl group, or [4] a C₁₋₈alkoxy group which may be substituted by a hydroxy group, m8h: 0˜2, m8i:0˜2, (7) a 4- to 10-membered heterocycloalkyl (C₀₋₈ alkyl) aminocarbonylgroup which may be substituted by oxo group(s), (8) a 4- to 10-memberednitrogen-containing heterocycloalkylcarbonyl group which may besubstituted by one or more R^(8D), R^(8D): [1] a C₁₋₈ alkyl group whichmay be substituted by one or more R^(8D1), [2] a hydroxy group, [3] aC₁₋₈ alkylsulfonyl group, or [4] a C₁₋₈ alkoxycarbonyl group, R^(8D1):[1] a hydroxy group, or [2] a C₁₋₈ alkoxy group, (9) a hydroxycarbonylgroup, (10) a C₀₋₈ alkoxy (C₀₋₈ alkyl) aminocarbonyl group which may besubstituted by hydroxy group(s), (11) a halogen atom, (12) a (C₁₋₈alkyl)_(m8j)-amino group which may be substituted by one or more R^(8H),m8j: 0˜2, R^(8H): [1] a hydroxy group, or [2] a 4- to 10-memberedheterocycloalkyl group, (13) a hydroxyl group, (14) a C₁₋₈ alkoxy groupwhich may be substituted by one or more R^(E), R^(8E): <1> a hydroxygroup, <2> halogen atom, <3> a hydroxycarbonyl group, <4> a C₁₋₈alkoxycarbonyl group, <5> a 4- to 10-membered nitrogen-containingheterocycloalkylcarbonyl group which may be substituted by one or moreR^(8E1), <6> a (C₁₋₈ alkyl)_(m8k1)-amino group which may be substitutedby one or more R^(8E2), m^(8k1): 0˜2, <7> a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(8E3),<8> a 5- to 14-membered heteroaryl group, <9> a (C₁₋₈alkyl)_(m8k2)-aminocarbonyl group which may be substituted by one ormore R^(8E6), m8k2: 0˜2, <10> a C₁₋₈ alkoxy group which may besubstituted by one or more R^(8E7), <11> a C₁₋₈ alkylthio group, <12> aC₁₋₈ alkylsulfinyl group, <13> a C₁₋₈ alkylsulfonyl group, R^(8E1): <1>a C₁₋₈ alkoxycarbonyl group, <2> a C₁₋₈ alkanoyl group, <3> a C₁₋₈alkylsulfonyl group, <4> a (C₁₋₈ alkyl)_(m8k3)-aminosulfonyl group,m8k3: 0˜2, or <5> a 4- to 10-membered heterocycloalkyl group, R^(8E2):<1> a hydroxy group, <2> a C₁₋₈ alkoxycarbonyl group which may besubstituted by halogen atom(s), <3> a C₃₋₈ cycloalkyl group which may besubstituted by C₁₋₈ alkyl group(s) which may be substituted by hydroxygroup(s), <4> a C₁₋₈ alkanoyl group which may be substituted bysubstituent(s) selected from the group consisting of [1] a (C₁₋₈alkyl)_(m8k4)-amino group and [2] a halogen atom(s), m8k4: 0˜2, <5> a(C₁₋₈ alkyl)_(m8k5)-aminocarbonyl group, m8k5: 0˜2, <6> a C₁₋₈alkylsulfonyl group, <7> a 4- to 10-membered nitrogen-containingheterocycloalkylsulfonyl group which may be substituted by C₁₋₈ alkylgroup(s), <8> a (C₁₋₈ alkyl)_(m8k6)-aminosulfonyl group which may besubstituted by C₁₋₈ alkoxycarbonyl group(s), m8k6: 0˜2, or R^(8E3): <1>a C₁₋₈ alkyl group which may be substituted by substituent(s) selectedfrom the group consisting of [1] a hydroxy group and [2] a C₁₋₈alkylcarbonyloxy group, <2> a C₁₋₈ alkylcarbonyloxy group, <3> a hydroxygroup, <4> a C₃₋₈ cycloalkyl group, <5> a C₁₋₈ alkoxy group, <6> a C₁₋₈alkoxycarbonyl group, <7> a C₁₋₈ alkylsulfonyl group, <8> a (C₁₋₈alkyl)_(m8k8)-aminocarbonyl group m8k8: 0˜2, <9> a C₁₋₈ alkanoyl groupwhich may be substituted by hydroxy group(s), <10> an oxo group, or <11>a 4- to 10-membered heterocycloalkyl group which may be substituted bysubstituent(s) selected from the group consisting of [1] a C₁₋₈ alkanoylgroup, [2] a C₁₋₈ alkoxycarbonyl group and [3] a C₁₋₈ alkylsulfonylgroup, R^(8E6): <1> a C₂₋₈ alkenylcarbonyloxy group, <2> a hydroxygroup, <3> a cyano group, <4> a (C₁₋₈ alkyl)_(m8k9)-amino group whichmay be substituted by hydroxy group(s) m8k9: 0˜2, <5> a C₁₋₈ alkoxygroup which may be substituted by hydroxy group(s), <6> a C₁₋₈alkylcarbonyloxy group, <7> a 4- to 10-membered heterocycloalkyl groupwhich may be substituted by C₁₋₈ alkyl group(s), or <8> a 5- to14-membered heteroaryl group, R^(8E7): <1> a hydroxy group, or <2> aC₁₋₈ alkoxy group which may be substituted by hydroxy group(s), (15) a4- to 10-membered heterocycloalkyloxy group which may be substituted byone or more R^(8F), R^(8F): <1> a C₁₋₈ alkyl group which may besubstituted by one or more R^(8F1), <2> a C₃₋₈ cycloalkyl group, <3> aC₁₋₈ alkanoyl group which may be substituted by halogen atom(s), <4> aC₁₋₈ alkylcarbonyloxy group, <5> a C₁₋₈ alkoxycarbonyl group, <6> a 4-to 10-membered heterocycloalkyl group which may be substituted by one ormore R^(8F2), <7> a C₁₋₈ alkyl sulfonyl group, <8> a hydroxy group, or[9] a C₆₋₁₀ aryl group, R^(8F1): [1] a hydroxy group, [2] a C₁₋₈ alkoxygroup, or [3] a halogen atom, R^(8F2): [1] a 4- to 10-memberedheterocycloalkyl group, [2] a C₁₋₈ alkoxycarbonyl group, or [3] a C₁₋₈alkylsulfonyl group, (16) a 5- to 14-membered heteroaryloxy group, (17)a 4- to 10-membered heterocycloalkylcarbonyloxy group, (18) a (C₁₋₈alkyl)_(m8l1)-aminosulfonyloxy group, m8l1: 0˜2, (19) a C₁₋₈ alkyl thiogroup which may be substituted by [1] (C₁₋₈ alkyl)_(m8l2)-aminogroup(s), [2] hydroxy group(s) or [3] hydroxycarbonyl group(s), m8l2:0˜2, (20) a C₁₋₈ alkylsulfonyl group which may be substituted by one ormore R^(8G), R^(8G): [1] a hydroxycarbonyl group, [2] a hydroxy group,or [3] a (C₁₋₈ alkyl)_(m8l3)-amino group, m8l3: 0˜2, (21) a 4- to10-membered nitrogen-containing heterocycloalkylsulfonyloxy group whichmay be substituted by C₁₋₈ alkyl group(s), (22) a C₂₋₈ alkenyloxy group,and (23) a C₁₋₈ alkylsulfonyloxy group which may be substituted byhalogen atom(s); R⁹ is selected from the group consisting of: (1) ahydrogen atom, (2) a C₁₋₈ alkyl group which may be substituted by one ormore R^(9A), R^(9A): [1] a C₃₋₈ cycloalkyl group, [2] a 4- to10-membered heterocycloalkyl group which may be substituted by one ormore R^(9A1), [3] a hydroxy group, [4] a C₁₋₈ alkoxy group, or [5] ahydroxycarbonyl group, R^(9A1): [1] a C₁₋₈ alkyl group, [2] a C₃₋₈cycloalkyl group, or [3] a 4- to 10-membered heterocycloalkyl group, (3)a C₂₋₈ alkenyl group which may be substituted by one or more R^(9B),R^(9B): [1] a (C₁₋₈ alkyl)_(m9a)-amino group, [2] a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more groupR^(9B1), R^(9B1): [1] a C₃₋₈ cycloalkyl group, or [2] a 4- to10-membered heterocycloalkyl group, m9a: 0˜2, (4) a C₂₋₈ alkynyl groupwhich may be substituted by one or more R^(9C), R^(9C): [1] a C₁₋₈alkoxy group, [2] a (C₁₋₈ alkyl)_(m9b)-amino group which may besubstituted by C₆₋₁₀ aryl group(s), [3] a 4- to 10-memberedheterocycloalkyl group which may be substituted by one or more R^(9C1),[4] a C₃₋₈ cycloalkyl group, [5] a hydroxy group, [6] a hydroxycarbonylgroup, or [7] a C₁₋₈ alkyloxycarbonyl group, m9b: 0˜2, R^(9C1): [1] aC₃₋₈ cycloalkyl group, [2] a 4- to 10-membered heterocycloalkyl group,or [3] an oxo group, (5) a C₃₋₈ cycloalkyl group, (6) a 4- to10-membered heterocycloalkyl group which may be substituted by one ormore R^(9D), R^(9D): [1] a C₁₋₈ alkyl group which may be substituted by4- to 10-membered heterocycloalkyl group(s), [2] a C₃₋₈ cycloalkylgroup, [3] a 4- to 10-membered heterocycloalkyl group, or [4] a C₁₋₆alkylsulfonyl group, or [5] a C₁₋₈ alkoxycarbonyl group, (7) a C₆₋₁₀aryl group which may be substituted by one or more R^(9E), R^(9E): [1] ahalogen atom, [2] a hydroxy group, [3] a hydroxycarbonyl group, or [4] aC₁₋₈ alkyl group which may be substituted by hydroxy group(s), or [5] aC₁₋₈ alkoxy group, (8) a 5- to 14-membered heteroaryl group which may besubstituted by C₁₋₈ alkyl group(s), (9) a cyano group, (10) a C₁₋₈alkanoyl group, (11) a 4- to 10-membered nitrogen-containingheterocycloalkylcarbonyl group which may be substituted by C₁₋₈ alkylgroup(s), (12) a halogen atom, (13) a (C₁₋₈ alkyl)_(m9c)-amino groupwhich may be substituted by one or more R^(9F), m9c: 0˜2, R^(9F): [9F-1]a C₁₋₃ alkylsulfonyl group, [9F-2] a (C₁₋₃ alkyl)_(m9f1)-aminosulfonylgroup (m9f1: 0˜2), or [9F-3] a C₁₋₃ alkanoyl group which may besubstituted by (C₁₋₃ alkyl)_(m9f2)-amino group(s) (m9f2: 0˜2), (14) aC₁₋₈ alkylcarbonyl(C₀₋₈ alkyl)amino group which may be substituted by(C₁₋₈ alkyl)_(m9d)-amino group(s), m9d: 0˜2, (15) a C₁₋₈alkylsulfonyl(C₀₋₈ alkyl)amino group, (16) a (C₁₋₈alkyl)_(m9e)-aminosulfonyl(C₀₋₈ alkyl)amino group, m9e: 0˜2, (17) anitro group, (18) a hydroxy group, (19) a C₁₋₈ alkoxy group which may besubstituted by one or more R^(9G), R^(9G): [1] a hydroxy group, [2] ahydroxycarbonyl group, [3] a C₆₋₁₀ aryl group which may be substitutedby C₁₋₈ alkoxy group(s), [4] a (C₁₋₈ alkyl)_(m9g1)-amino group, [5] aC₁₋₈ alkoxy group which may be substituted by one or more R^(9G1), [6] a5- to 14-membered heteroaryl group, or [7] a 4- to 10-memberedheterocycloalkyloxy group which may be substituted by C₁₋₈ alkylgroup(s), m9g1: 0˜2, R^(9G1): [1] a C₁₋₈ alkoxy group, or [2] ahydroxycarbonyl group, (20) a 4- to 10-membered heterocycloalkyloxygroup which may be substituted by [1] 4- to 10-membered heterocycloalkylgroup(s), or [2] C₁₋₈ alkoxycarbonyl group(s), (21) a C₁₋₈alkylsulfonyloxy group which may be substituted by halogen atom(s), (22)a C₁₋₈ alkylthio group which may be substituted by (C₁₋₈alkyl)_(m9f)-amino group(s), m9f: 0˜2, (23) a C₁₋₈ alkylsulfonyl groupwhich may be substituted by (C₁₋₈ alkyl)_(m9g)-amino group(s), m9g: 0˜2,(24) a (C₁₋₈ alkyl)_(m9h)-aminosulfonyl group, m9h: 0˜2, (25) a 4- to10-membered nitrogen-containing heterocycloalkylsulfonyl group which maybe substituted by C₁₋₈ alkyl group(s), and (26) a hydroxycarbonyl group,or a salt or solvate thereof.
 12. The method of claim 11, wherein themethod comprises treating cancer or cancer metastasis in the subject inneed thereof.
 13. The method of claim 12, wherein the cancer is selectedfrom the group consisting of lung cancer, anaplastic large celllymphoma, inflammatory myofibroblastic tumor, esophageal cancer, andneuroblastoma.
 14. The method of claim 11, wherein the method comprisestreating depression or cognitive function disorder in the subject inneed thereof.
 15. The method of claim 11, wherein the pharmaceuticalcomprises as an active ingredient a compound selected from the groupconsisting of9-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1l-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(1-isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;8-(2-tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;and9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile,or a salt or solvate thereof.
 16. The method of claim 11, wherein thepharmaceutical comprises as an active ingredient9-ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile,or a salt or solvate thereof.